Episode Transcript
[00:00:00] Speaker A: Foreign.
[00:00:09] Speaker A: My name is Krishna Shah and I am a Gastroenterology Registrar and IBD Research Fellow at the Royal London Hospital and the current training representative for the BSG IBD Committee. It is my great pleasure to host this episode as part of the series on the newly published BSG IBD guidelines with a focus on advanced therapies in ulcerative colitis.
I am pleased to be joined by Kamal Patel who is a consultant gastroenterologist at St George's Hospital, the Co lead for IBD Research and clinical at St. George's Hospital and also a key opinion leader in research and clinical trials in the IBD community.
Thank you so much for joining us.
[00:00:52] Speaker B: Thank you and I am delighted to.
[00:00:53] Speaker A: Be here over this episode. We're going to go over the Advanced Therapies in Osteocolitis section of the new BSG guidelines and I thought it would be great to starting with, talk about the criteria for escalating to advanced therapies, review the landscape of the different advanced therapies available, reflect on the key updates since the last guideline, and then as we have you an expert in this field, it would be really good to reflect upon your real world practice and hear about how you approach the guidelines and how you approach the different aspects of UC care.
So I think it would be really good to perhaps give us a definition of advanced therapies in IBD because there is lots of variation between different clinicians and what they define in advanced therapy.
[00:01:43] Speaker B: Is so this is a very important question and it can actually differentiate between paper to paper in these guidelines we have been very clear the entry treatment for ulcerative colitis is of course mesalazine and the guidelines still give that flavor. And there is no change from the last two iterations of the guidelines with respect to this. But of course mesalazine is not perceived to be an advanced therapy and the definition for mesalazine in any paper is that it is conventional therapy and not advanced therapy.
Now in routine clinical practice it's a case by case decision. But the entry point treatment for ulcerative colitis of course remains mesalazine, with or without a course of prednisolone. And that's a clinical decision which obviously I can't explain over a podcast. But those two treatments remain. The entry treatment for mesalazine, either as a combination or two weeks of Mesalazine, if there isn't adequate response, which actually we do say in the paper in this set of guidelines should be approximately a 30% improvement within the first two weeks, then if you haven't escalated to prednisolone, you should be escalating to prednisolone.
Now again, whether we talk about prednisolone or non systemic oral corticosteroids, they are also not considered advanced therapies. And again, the guidelines has suggested that you can use non systemic corticosteroids as well. But the patients you would think about using this is either someone who hasn't tolerated mesalazine as a initial monotherapy or an individual with left sided disease where you may want to give an 8 week course to 12 week course of a non systemic oral corticosteroid with oral mesalazine. And then of course, in the guidelines, topical therapies are extensively discussed, but these are also not considered advanced therapies. And really our practices is to use mesalazine in combination with a topical mesalazine for, for anything beyond mild uc.
So any moderate to severe initial presentation escalate within two weeks to an oral corticosteroid. And to be honest, most of the times I do just favor oral prednisolone because if you need an escalation, I would prefer to do it with a more potent one where they haven't had a clear improvement. So the 30% improvement is what I ask patients, have you had this improvement within the first seven to 14 days? And I would escalate. And then if you're not responding to steroids, there is no role for immunomodulators.
And we have made this very clear in our guidelines that immunomodulators and the only immunomodulator which we have suggested for use is azathioprine is in the context of someone who has had a good response and actually a full remission to oral corticosteroids.
Now, from a practical perspective, you wouldn't know that we start them in conjunction. You start the prednisolone with the azathioprine and azathioprine and mercaptopurine are of course interchangeable here. But you would start the thiopurine with your prednisolone. And if you haven't responded to that early, within two to four weeks, you would then escalate. And certainly if you haven't responded in eight weeks, you will then escalate. And then treatments beyond mesalazine, corticosteroids and thiopurins is what is considered to be an advanced therapy.
[00:05:12] Speaker A: Okay, so we're going to put all biologics and small molecules under that term?
[00:05:18] Speaker B: Yes.
[00:05:19] Speaker A: Okay.
[00:05:20] Speaker B: And what I have Mentioned there is what we refer to as conventional therapies. And you know, this is in keeping with how the clinical trials differentiate between conventional therapies and advanced therapies in the new age. You know, we're in the era now where a lot of small molecules are considered advanced therapies.
[00:05:38] Speaker B: Which is completely fair, completely justifiable. And of course these drugs also sadly fit the high cost drug real clinical pathways. So it's also clinically appropriate to put them in the same sort of box as biologics.
[00:05:52] Speaker A: Okay. And so you've highlighted there quite nicely the criteria for escalating to an advanced therapy. So you've talked about failure to respond to conventional therapy or refractory disease. Are there any other high risk features that may point you towards escalating a patient earlier towards advanced therapy? I know it's obviously different domain to Crohn's disease and the evidence for top down therapy is stronger in Crohn's disease, but are there any features within the ulcerative colitis phase?
[00:06:21] Speaker B: So, you know, this is a very interesting question and sadly we're still in a situation where our clinical trials haven't been able to answer this question.
So we do not have a step up versus top down treatment in ulcerative colitis. I haven't actually even heard one of being deployed in uk. I'm hearing some whispers that there might be a miracuzumab versus azathioprine after patients have failed mesalazine, but I haven't seen this come to the UK yet.
Hopefully it will, it will be a very good clinical trial.
So there isn't any clear cut definitions except for acute severe ulcerative colitis, which is a very different phenotype, which we have again been fairly clear in the guidelines, of course, always needs intravenous corticosteroids and then either needs escalation because of a rescue intervention being needed, which approximately 70% of patients will need, or we'll need starting with an advanced therapy based on the recent clinical trial, the Active trial in France study with the trial used infliximab and azathioprine as the intervention. But in the guidelines we've been a little bit more flexible and we've said you can consider starting any advanced therapy even if they respond to intravenous corticosteroids. That's the only high risk phenotype where there is a suggestion that we shouldn't wait to, we shouldn't delay starting the advanced therapy. Which advanced therapy to start in somebody who has responded to intravenous corticosteroids is based on local access. For us, our access is straightforward for filgotinib or etrazomod in those patients.
So that's what we would use for somebody who has had a nice response to intravenous corticosteroids that's purely based on our ICB and of course biased because of reimbursement criteria. But I don't think you're wrong to use many treatments in that condition. In that option of acute severe uc, you know, a bridge to Ustekinumab, a bridge to edilizumab, bridge to infliximab. Azathioprine is also completely acceptable in those situations. Of course, we have newer agents as well which are completely acceptable to use, but the cost could be prohibitive. So bisimilar or one of our cheaper, newer, advanced therapies, I suspect, will be the practice in most of the country, hopefully in these patients.
[00:08:47] Speaker A: And you raise a really important point there, because the landscape is filled and is filling rapidly with lots of neuroagents. And we do work in a National Health Service. So we do need to take into account cost and local guidelines. And so while we have the BSG guidelines that give us really good guidance, we obviously need to take these aspects into account.
So I thought we could now move on to the different classes of drugs and talk about any key updates or new areas of research within the different classes. And perhaps if we start with anti tnf, as we're most familiar with this class, and if we take infliximab first. So the guidelines suggest infliximab for induction and maintenance.
It's used for rescue therapy. In acute severe uc. There's a separate episode focusing on acute severe uc. So we'll move away from that.
Can you walk us through perhaps, your approach to initiating this? And I think the part that I would be more interested in is the maintenance therapy and where you use IV versus subcutaneous treatment.
[00:09:52] Speaker B: So, again, this is a very relevant question for 2025 clinical practice because it's only really in the last three years we've had access to subcutaneous infliximab, and of course we're learning about subcutaneous infliximab. One of the sad realities in the ulcerative colitis section from the data we have, is we could not find any good quality studies to clearly differentiate in which cohort we should use subcutaneous maintenance over intravenous maintenance or vice versa.
And we couldn't really find any evidence to make any form of Committed statement, whether it be a grade statement or a good practice statement with respect to how to use maintenance in terms of the delivery, I think, of course it goes without say where induction of infliximab has worked.
You absolutely need to continue some form of maintenance. Infliximab.
And the evidence in ulcerative colitis would favor always using infliximab with azathioprine in combination in induction.
And again, the evidence, which is not a huge piece of evidence, but the best evidence which we could see available would suggest that in ulcerative colitis there is an additional benefit of continuing the azathibrin maintenance.
And therefore we weren't able to routinely recommend, like in Crohn's disease, where we have the spare trial, we weren't able to routinely recommend the azathioprine can be withdrawn.
Now, you know, as I've explained in the methodology section, guidelines have to be absolutely transparent to the evidence we have available.
And then of course, clinical practice is pragmatic and the patient opinion also comes in.
If you gave the patient a choice to continue on monoinfliximab versus combination infleximab, I think most patients would prefer just to be on one drug. And that's of course also balanced because of the side effects of azathioprine. And you know, this is not like 2010 where we didn't have choices, we have choices now.
So my approach to infliximab, and this is my own opinion, because we weren't able to formulate this or specifically give a good practice statement on this in the guidelines, is that we will start with an intravenous induction of infliximab always.
And we will start with azathioprine, ideally at the time of the first dose of infliximab or even better than that, a few weeks before.
And we will give usually three intravenous induction doses and we will aim for drug levels of between, ideally again between 10 to 20. So we're aiming a little bit higher than what the evidence suggests. Optimize the dose of infliximab then needed intravenously to try to get somebody into that TDM level with intravenous infliximab and then give the patient the choice to say, now do you want to have subcutaneous maintenance once that target has been reached, or do you want to continue on intravenous infliximab and then it's a patient driven choice. At the moment, we're quite fortunate that our infusion suite still has capacity to give the patient a choice. If your infusion suite doesn't have capacity to give the patient the choice, it is completely acceptable to then switch them to subcut maintenance. After the three induction doses, as long as you've had a look at TDM and hit your local target and then the azathioprine, we will discuss patient by patient.
So if an individual has got drug levels over 10 without antibodies, then we're quite happy to withdraw the azathioprine after explaining to the patient that actually you might get 5 to 10% more continuing the azathioprine. We're not talking about a game changer changing figure, we're talking about minimal gains.
And if an individual had been very sick and wants to continue the azathioprine, then I won't say that's absolutely. No, that's not unreasonable, but the patient is involved in that part of the decision making process.
Now, this is not talking about acute severe UC patients, okay? Acute severe UC patients, actually most of them. My practice is to give an intensified accelerated dosing regiment. It's been impossible for anyone to comment on what the correct dose of infliximab is in acute severe ulcerative colitis. You know, the latest clinical trial from Australia showed that the first dose doesn't make so much of a difference whether you give 5mg up front or 10mg up front. It is with the caveat that that cohort of patients had slightly more towards Mayo 2 than Mayo 3, endoscopy averages and albumins around the 30 mark. And those are not the patients which I'm worried about, it's the UCIS 7, 8 patients and the albumins under 30 who seems to be most of our admissions actually, but not in the clinical trial where I think you need a more intense infliximab regime. And an acute severe UC patient at St. George's our practice is we give them a sort of accelerated intensified dosing regimen of infliximab with we start the azathioprine as soon as we've got the TPM key and we don't do any withdrawal until we've had endoscopic confirmation that they have got at least a Mayo one and ideally a Mayo zero before we withdraw.
So I respect the higher risk phenotypes and give them the benefit of combination. But your standard moderate to severe patient is usually around the six month mark where we have optimized drug levels, got them onto subcarp maintenance if that's what they want, and then you have the decision of withdrawing the azathioprine. And you know, just to clarify, I wouldn't necessarily scope that patient for making a drug changing decision. That patient, I'm happy to go on calprotectin and nicely, the BSG has given CalProtectin definitions as well for the UC cohort and the targets to aim for.
[00:15:50] Speaker A: That's really helpful.
So are there any parts of the guidelines that highlight any new information about how we should be using infliximab or do you think this is all conformation confirming that our current practices can continue?
[00:16:07] Speaker B: I don't think there is really any new information since the last iteration of guidelines for infliximab in ulcerative colitis in moderate to severe patients.
So the flavor is very similar. There is this time a statement on actually thiopurine withdrawals. And it's as I've explained, it's not clear cut and we couldn't completely say like we were able to in Crohn's disease.
How we have worded it is that the withdrawal of the thiopurine is associated with the risk of flare.
That's how we've worded it. And then in the summary, the odds ratios and the percentages are there.
[00:16:44] Speaker A: Yeah. And as you said, it's really important to be transparent about the data. So I think that's quite helpful for clinicians using the guidelines as a reference to then make their own clinical decision based on it.
[00:16:56] Speaker B: And we shouldn't forget you can show the patients how this is written and show them the figures. So then the patient can also be a little bit more part of that decision making process.
[00:17:06] Speaker A: Yeah.
Okay, so let's move on to, I guess one of the key recommendations from the guidelines. And this is about the role of adalimumab in ulcerative colitis.
So can you tell us a little bit about what drove that change?
[00:17:22] Speaker B: Okay, so for everyone, just to be fully clear on this, adalimumab was not suggested as a treatment for moderate to severe ulcerative colitis in the latest iteration of the BSG guidelines. And this is a conditional recommendation.
Actually, all of the advanced therapies have a conditional recommendation. And just to touch on this, what the word conditional means is that there is a little bit of transparency between the people who analyze this data to say that at the moment the data would suggest, with our methodology, which we used, we should not suggest adalimumab. But this could change in future with new data.
Now the adalimumab statement has caused discussions in the country.
I think it may have also Upset a few units with the way it's come across, which I completely understand because there will be patients who will read these guidelines who have been on Adalumumab, the highest prescribed biologic in the world, and will now be thinking, why has this happened?
First thing to say is if a drug has worked, it's very clear in the guidelines, just because there has been a change in the statement, do not change the treatment this time round. We had set a priori magnitudes which had to also be hit for us to recommend a treatment.
Now these a priori magnitudes were sacked before we looked at any of the actual.
[00:18:55] Speaker B: Data which the internal team, who are Cochrane experts, then produced for the clinician to make the grade statements.
And the a priori magnitudes were also defined by the entire working group. So this was not one individual, it was over 100 people.
And yes, the magnitude is based on that individual's opinion of what effect should be hit in a 2025 practice for a drug to be suggested or for a drug to be recommended, depending on, you know, the readout of the individual drug.
It's quite important that this practice is not something which the BSG decided to do on their own intuition. This is something which actually the World Health Organization, in collaboration with the GRADE Pro team, who have defined how GRADE statements are devised, they have actually recommended that this is the methodology which should be used.
You know, with the understanding in 2025, where we have so many treatments available, there should be some attempt to differentiate treatments with have minimal effect, moderate effect, large effects to less than minimal effect.
Clinical trials are of course different, okay? It's impossible to say that the population in one clinical trial exactly mirrors another clinical trial. And also the methodology of clinical trials are different as well. So induction in most of these clinical trials is not the same week, it's a different time point.
And you know, these are differences which is impossible to adjust for on any methodology at this time point, in the absence of head to head clinical trials which cover all of our agents. And that's just impossible. Let's be absolutely real.
So we've used a network meta analysis, but not to compare against the drugs, to compare the effect against a unified placebo to see then what the effect of each drug comes out to be. And then also, of course, we have then looked at that effect to the effect in the actual registrational study itself, just to make sure there wasn't a massive difference.
We then presented this data in a big meeting to the entire working group of the guidelines. And sadly, adalimumab did not hit the minimal threshold which we had set a priori.
Now, the same applies to methotrexate.
Okay? And although we're not discussing our conventional immunomodulators today, so hence, if you look at these guidelines, methotrexate is not recommended. And this is differences actually to the European guidelines.
So methotrexate is not suggested, and adalimumab is not suggested because it did not hit the threshold of a minimum effect over placebo of 10%, either in the clinical trial or in our net network.
[00:21:52] Speaker A: Okay. And then you. But you do highlight, which I think is a really important point, that if they are patients who are already established on these drugs and they're stable, this does not mean that they should be taken off these treatments. So they should continue on Adalimumab if they are.
[00:22:07] Speaker B: Well, absolutely, because, look, the guideline is not there to say the drug doesn't work.
We know the drug worked, it hit a P value.
[00:22:18] Speaker B: But with the methodology we used, it's a drug with the guidelines are no longer suggesting for new starters for patients, you know, really from the middle of.
[00:22:27] Speaker A: This year, do you think that there are any indications.
[00:22:33] Speaker A: For starting a patient on adalimumab if, for instance, they had an extra intestinal manifestation like an axial spondyloarthropathy?
[00:22:43] Speaker B: So, absolutely. You know, you hit the nail on the head there. And this is where it's not just about the headline. You have to read the text. And in the text we also explain that if somebody has ankylosing spondylitis or another ankylosing spondylitis I mentioned, because it's usually the one where we would favor adalumumab. But if they have another extraintestinal manifestation which can be covered with adalumumab, absolutely, that's absolutely fine. Okay. What, what the word conditional means, okay, from a grade perspective in the recommendation, is that you appreciate that there are other alternatives for that individual when you can strongly recommend something. What you're saying is that there isn't another alternative as good as the one which you are putting to the patient. So what conditional means is there are alternatives. Now, as I said, all of the statements are conditional, all of the drugs are suggested, and adalimumab is the only advanced therapy which is not suggested.
But the word suggested also gives the clinician a bit of leeway.
That's how the data reads out from my own perspective. I just think it's important. If you're putting a patient on UC with adalimumab today, the clinician has thought it through. Okay. I don't think there's any debate. It's of the anti TNFs we have, infliximab is the best in UC and that's infliximab with azathioprine. That should not be a controversial statement. Infliximab and azathioprine is a better anti TNF in uc.
Anti TNF is also perhaps our most important drug in UC at this time point because we don't have another drug class approved for acute severe UC in our conventional advanced therapies. Cyclosporine is getting increasingly more difficult to utilize in this situation because we just don't seem to have the resources to deliver it properly on a ward anymore. A lot more faffing about getting the levels with cyclosporine and you know, just generally there's a lot more anxiety in using cyclosporine. So again, you know, if you're using an anti tnf, my own perspective on this is why are you not potentially saving it for acute severe uc?
And if you're using one, why are you not using the best one available? I don't think it's personally and this is my own, you know, I don't think it's fair just because adalimumab is so cheap to bypass infliximab and then if you've given a UC patient adalimumab, you have compromised their response to infliximab. It's not that it's absolutely not going to work, but you've taken away more than 80% of your chance of infliximab working.
[00:25:16] Speaker B: So you've affected the whole class. And also then the immune clearances and escape mechanisms and upscaling a patient once they fail the first advanced therapy. We are nowhere near understanding all of that properly.
The way the BSG data came out on Adalumab is of our advanced therapies it was the weakest.
That also holds true actually to every network meta analysis I've seen.
So it's not just the BSG network which has seen this and you know, the living guidelines from the American Society are also saying it's the least preferred option.
So they haven't given it the terminology of not suggested, but it is in the least preferred box.
[00:26:00] Speaker A: Well, that was going to be my next question was you mentioned that it has caused some debate and discussion within the across the uk. How is the global or European IBD societies responded to this?
[00:26:16] Speaker B: So I haven't spoken to this with experts in Europe or USA directly Looking at the American guidelines, it's whether you call a drug not suggested or your least preferred option, you know, in day to day English that's interchangeable in my opinion. So it's in keeping with the AGA guidelines. Echo didn't use a network meta analysis and they didn't use the GRADE methodology which we utilized.
I wasn't part of the ECHO guidelines, so I'm not sure why they took it chose that process with the BSG guidelines. What I can say is that Morris Gordon and Gordon Moran took this method on the key the senior team who wrote the methodology for the guidelines with the then the, the team members. So for uc, that was myself and Belcock, we went to Amsterdam, all of the team leads went to Amsterdam to understand what this methodology means. We all accepted that at this time point it's the best we have available. That's not to say it's absolutely the correct one, but it's the best we have available.
And then when we set our a priori magnitudes, you then can't change that magnitude to fit the scenario. Then we had to be true to the outcomes and we've been true to the outcome.
You know, from my own perspective, I haven't used Adalimumab in UC for more than five years because when cost wasn't an issue, you would not even be asking why are you not using infliximab in uc?
The default for me for a long time has been infliximab and azofibrin is the preferred way for me using anti TNF in uc.
And adalimumab is the exception way for those patients who have another reason why you should be using it. And generally I like reserving my anti TNF for acute severe uc. That's been my practice for many, many years.
[00:28:10] Speaker A: Okay, so perhaps reflecting a little bit on Gilimumab, where do you see the role of glimimab and is it something that you use in ulcerative colitis?
[00:28:20] Speaker B: So at St. George's Hospital we've got less than five patients on guillimumab. These are legacy patients and transfers from other hospitals.
The strength of recommendation for all of the drugs was conditional, so the grade statement will still read as a suggested option. And the certainty of evidence was low and the magnitude of effect was small.
Infliximab had a better certainty of evidence, again in the way the methodology of the grade works.
So again I generally with my experience with infliximab, tend to use infliximab over Galimumab. We now have a subcutaneous option for infliximab. So it's not like five years ago where we were going to add Alumimumab for those patients who wanted a subcutaneous option, or to Glimumumab for those patients who wanted a subcutaneous option. Look, I think I have to be honest here. From a UK perspective, glimumumab is a difficult drug for any of us to comment on because it hardly took off in UK and there must be a reason for that.
At St George's we actually ran the clinical trials for Guillimumab and it was my colleague, Professor Pollock, and we didn't have good internal experience with them, so we've tended to stay away.
Very interestingly, they may be making a comeback in combination programs in the future in the duet studies. But I think at the moment, Colummab is not a drug which is commonly used in uc.
And because it doesn't have any extra intestinal manifestation which it cross covers, that's part of the reason why it hasn't taken off.
[00:29:58] Speaker A: Okay, so moving on to the oral S1P receptor modulators. So Zanamod and Etrazimod are new entrants into the guidelines since the last version in 2019.
So how do they fit into your, your treatment algorithm and are they particular patients that you would reach for these drugs? I know you mentioned, for instance, acute severe UC patients who are very steroid responsive. That might be a group of patients where you would use this advanced therapy on or other groups of patients. Have they worked well for you?
[00:30:33] Speaker B: So from the BSD guidelines perspective, both of them of course, are suggested drugs.
The way the trials were designed has meant that the magnitude of the effect of the drugs in the BSG paper looks a little bit different between Etrazimod and Ozanomod.
So the trials were actually very dissimilar in the design in that Ozanomod was a trial which had an induction phase and then responders were re randomized and Etrazimod was a treat through design.
Now, in a treat through design, the way the methodology for grade works is you cannot have maintenance data.
So the magnitude of effect for Etrazomod is only based on the induction data.
Okay. And this is why one of my key messages today is that all of the drugs have a conditional recommendation and they are all suggested. Upadisitinib is the only one which hit the magnitude for a recommendation based on the grade statement.
But don't get too caught up in that. All of those drugs are okay to Use. It's not a hierarchy, okay? It's the transparency of the readout of the data.
And in a way I wish this was sort of in a supplement and the clinician headline was just that, you know, in accordance with our local access pathway, you can use Etrazomod, you can use Filgotinib, okay? You can use Upa, Tofa, whichever drug you pick. The only one which we have not suggested using is Adalimumab. So that's my real take home message. With Etrazomod and Nazanomod there has actually interestingly been more clinical trials on Intrazumod which have been now.
[00:32:10] Speaker B: Responders being re randomized like the Ozanomod trial and it would actually change the magnitude of effect.
Okay. But that trial only was released. The outcomes of that trial were only released a month ago. So we didn't have it when we did the BSG summary. And that's also why these are conditional statements, because we know new data is going to come out which is going to change the certainty of evidence and the magnitude of effect for a lot of these drugs over the next five years.
And again, part of grade is you have to keep updating the guidelines because it appreciates that we do not know enough about any drug really.
The only exception here is Mesalazine which has had 50 clinical trials, but we don't know enough. Most of these drugs here have less than five clinical trials. When you combine the induction and maintenance trials we have.
So Etrazimod and Nazanomod have both been suggested.
How we use them at St. George's is driven by the cost of acquisition.
So Ezanamod sadly has been priced out, which I think is what's happened in most of the country.
And Itrazumod, the nice ta, allows you to use it first line.
It's a drug which our early experience, and we have only been using it for just over a year now, shows that it does work for moderate to severe UC patients. It works quite well in my opinion, when you use it earlier than later. Now of course that applies to all of the drugs, but this is. Etrazomod is a drug which I would rather use early than late.
And it's an oral option which UC patients quite like because they're used to. A lot of them are used to taking Mesalazine.
So we will use it in parity with a couple of other drugs in our first.
[00:33:52] Speaker B: Drug space.
[00:33:53] Speaker A: Okay. And just some practical information about how you use it. So how do you on a clinic basis work through getting the ecg, getting the eye tests and streamlining all of that.
[00:34:05] Speaker B: Okay, so of course this is a practical question. The guidelines do not go into that level of detail.
But you have to do the standard drug screen, chest X ray, for reasons which I don't fully understand, because actually I would argue you don't need to do most of that for etrazomod, but you have to do your standard immunosuppressive screen and your chest X ray ecg. I would hope most hospitals have a walk in service so you request it.
[00:34:31] Speaker B: Ours is all electronic requests, so we would request it electronically and send the patient for a walk in ecg, the eye test through our virtual biologic immunosuppressive clinic and our advanced therapy clinic.
One of the nurses would contact our internal eye department to make them an appointment. Within three months, most patients can have the eye test alongside initiating the drug. It's only high risk patients who need the eye test first. And you have the option of just going to your local.
What are they called?
[00:35:00] Speaker A: Opticians.
[00:35:01] Speaker B: Yeah, opticians, yes. And just paying. It's between 10 to 20 pounds, so it's not a massive cost. But obviously the patient would have to know they would be picking up the cost.
And if you are opting to do it that way, be very clear with the patient that they don't just bring the pictures back, they actually bring the formal report back. Otherwise you will be interpreting pictures. Because we've had that for a few patients who have been and then we've had to go back to them and said, can you actually get us the full report, please? Not just the yep. I think it's very important you have in your service with any new drug because we're learning about these drugs and this is where the real world, actual experience becomes so important. It's real world for me is more about practicalities and complications.
It's very rare. A drug which becomes approved doesn't work.
But the real. So the real world is about, you know, more about the nuances of it and we need to see are there any side effects with these class of drugs which were not picked up in the clinical trials. They seem very safe to me. But are there any side effects? And you know, if all of us in UK are struggling to get eye tests, then obviously that is a problem and we have to learn from our community.
I think in teaching hospitals we're a little bit luckier because access to specialist services a little bit easier. But I do feel for our DGH colleagues. But it's important to know that if you don't have a local ophthalmology service either. You reach out to the tertiary service which is catering your trust for this, to try to see if they will take these patients on. Or then the sad reality of the patient having to pay between 10 and 20 pounds to have a, to have the eye test. You know, when I said in acute severe UC patients, I just gave you that our first line drug use for advanced therapies is usually etrazomod or Filgotinib. And that's purely driven by our local cost and the reimbursement for, you know, for a standard patient who is in context of ASAC made a very good response to intravenous steroids. But in a mild to moderate patient, this is somebody who's been struggling on whatever treatment, conventional treatment they've been on.
[00:37:07] Speaker A: Okay, so perhaps we can move on to JAK inhibitors. And we have three JAK inhibitors to pick from. Does the BSG guidelines give us any advice on how to pick between the three?
[00:37:23] Speaker B: It doesn't, because on the evidence which we have, there is no head to head. And as I said, the network which we performed was not to compare the drugs to each other, it was to compare the drugs to placebo.
And this is a, you know, this is an area which sadly has been misinterpreted.
So when you look at the JAK statements, Upper has been recommended and that's because the data showed it had a magnitude of effect over 30%.
[00:37:55] Speaker B: The certainty of evidence with upper diecitinib comes out as high. And that's because, purely because they had two induction trials which were designed exactly the same.
So when you compare this to filgotinib which had one induction study which had exclusively bio naive patients and another induction study which had exclusively bio exposed patients, of course you're going to get different results because the populations are different. But because the outcomes don't mirror each other and the populations don't mirror each other, it downgrades the certainty of evidence of filgotinib because of the trial design.
Whereas Upper's trial design is very good from a grade perspective because automatically the certainty of evidence is at the highest certainty. When you have two clinical trials and then any drug which has a dose dependent effect which you again see with uppadesitinate but you don't see with Filgo because the lower dose didn't work, again you have more confidence. It's the drug which is working.
So it's important to point out, even in the infliximab registrational studies, 10 milligrams did not look any different to 5 milligrams.
[00:39:04] Speaker B: But when you look at the upadisitinib data, you can see there are deltas between the higher dose and the lower dose. Same with Tofa.
Okay. So the nuances of the grade have different certainty of evidence statements. For filgotinib, UPA and tofacitinib. It's to do with the trial designs and the effect of dosing. And then the magnitude of effects come out large for upadisitinib and tofacitinib and come out moderate for filgotinib.
But again, my take home message is that all three of these drugs work. You have to use it for the right patient in front of you.
Okay. Based on local practices. So what do we do at St. George's Hospital? And sadly, this is driven by cost.
But also there's an inference to side effects which is not looked at all in a guideline is that for moderate patients we will go with filgotinib because it's the cheapest. That's the truth. And then for more severe patients and for patients who have risk of hospitalization, or for a patient where they have a contraindication to a steroid, high inflammatory burden at baseline, we will always favor upadisitinib.
And you know, I wouldn't have picked upadicitinib for my own trial, which I'm running with Seb and Tim, if we did not think the data showed it worked the quickest.
[00:40:25] Speaker A: And I think it's really important to talk to you about that. But we'll come to that. The IKESO study towards the end. But so you've sort of highlighted really good situations where you can use upadacitinib and filgotinib. And I know this is not in the guidelines, but can I push you further to perhaps tell me how do you then differentiate between tofacitinib and filgotiniber?
[00:40:46] Speaker B: So tofacitinib, because it's twice daily, I think, has just lost its place. When you have three drugs, one is always going to take a hit. And tofacitinib has not taken a hit because of efficacy, it's taken a hit because most patients prefer once daily preparation to twice daily preparation.
And you know, on the data you can't really differentiate between tofacitinib and upadisitinib.
My personal.
[00:41:14] Speaker B: Experience is that upper in the first eight weeks is a little bit faster acting in the maintenance period, I don't think. Then there's any difference. And that's partially because we dose reduce upper dacitinib after 8 to 16 weeks. I think tofacitinib is a very good drug. But if you gave the patient an option, do you want a once daily drug or a twice daily drug? They're going to pick a once daily drug. I think there is, and again, this is my opinion, a side effect difference between Upadacitinib and filgotinib. So Filgo, again because it's probably under dosed compared to UPA has less side effects. And that's also why for moderate patients it's not just about the cost. There is a side effect preference as well from a Filgottenib point of view. So, you know, in the UK publication Shahid Ad Din was part of this in shingles.
Filgotinib in the systematic review is much closer to an anti TNF and actually has less risk of shingles when you just look at the absolute numbers than our anti TNFs, whereas upadicitinib and tofacitinib are the highest risk for shingles.
So there is, you know, side effect differentiators and I'm using shingles. But in fact in real clinical practice we don't actually really see many side effects with filgotinib if I'm going to be honest, and I quite like using it. And we're working on an easy switch of patients to Filgotinib to UPA for the partial responders and that's the optimal way for our local reimbursement. So that's what we're working towards and that's purely because of cost.
You know, just going back to the point on the BSG guidelines, you're okay to use any of the three JAK inhibitors and in the absence of head to head, there is no absolute differentiators between the three drugs. The reason why Upadisitinib is recommended and the others are suggested is it's the drug which has both a high certainty of evidence because of the way the clinical trial was designed, as well as a large magnitude of effect. And you know, again, I don't think that's unique to the BSG guidelines. If you look at all of the network meta analyses, I haven't seen an NMA in UC where at least in the induction period UPA isn't the highest ranked drug.
[00:43:26] Speaker A: That's really clear. I have a couple more questions about the JAK inhibitors. One of them is does the BSG guidance give you any advice about dosing in tofacitinib. So for instance, any period where they should before, they should reduce down to 5mg dosing. Is there any advice on that in the guidelines?
[00:43:48] Speaker B: There isn't in the guidelines.
The clinical way we used to use Tofacitinib, we've still got 40 to 50 patients on tofacitinib. So I should still say that the patients who responded to Tofacitinib, we haven't switched.
We did a flexible sigmoidoscopy, usually before de escalation, because you can use the same high induction dose in maintenance with Tofacitinib, this is not like upadisitinib, where there's a forced reduction in dose.
And because it was a new drug, and because whenever a new drug comes in, you've got a sicker cohort of patients going onto the drug.
We were cautious and we used somewhere between a 12 to 16 weekend endoscopy to check. And it was only really the patients who had full, not histological, we did not use histology, but a full Mayo response of a Mayo zero endoscopic score where we dose reduced them.
Could we have used calprotectin? We could have used calprotectin, you know, with a threshold of somewhere between 200 and 250. But with the new drug in my practice, I was taking it cautious and we were doing endoscopic evaluations.
I should point out patients who were reduced to 5mg BD had a higher risk of flaring. And the data for tofacitinib also shows this. Same with Upadisitinib, if you're on upper 15 milligrams versus upper 30 milligrams, you have a higher risk of flaring. The main driver for dose reduction here, unlike anti tnf, is because of side effects. So, you know, in anti tnf, we're comfortable giving the higher doses without worrying we're giving the patient an increased risk of side effects. With JAK inhibitors, that's not true. Higher dose also equates to higher side effects. Where we are at the moment is at St. George's with the upper dasitinib patients. Most of them will go on 30 maintenance because again, it will be a sicker cohort of patients who ends up on upper.
And I will do an endoscopic evaluation before reducing their dose.
Now, this is not mentioned in the BSG guidelines. This is my.
[00:45:50] Speaker A: I think it's really useful to reflect on your practice. And then again, I know this is not in the BSG guidelines, but do you have any of your own personal reflections on sequencing between JAK inhibitors?
[00:46:02] Speaker B: So, sequencing between JAK inhibitors, you know, very topical at the moment. There's no statement on this on the BSG guideline because there is no randomized control data. It is all real world evidence.
And you know, again, just to point out on the Oxford criteria of evidence, and this is not our fault, real world evidence has been deemed to be the lowest quality of evidence.
So you cannot make grade statements on low quality evidence. You can make best practice statements if you have enough real world evidence where you know the signal from multiple sources of real world evidence with a high number of individuals in each cohort shows the same signal. And in other conditions where this has been done, we're talking about thousands of patients showing the same signal.
Like kind of in the COVID era where we had studies which were a lot more pragmatic but had thousands of patients, so it was easier to see a signal that it's, you know, without sticking to strict clinical trial criteria, the volume of patients meant you were taking away any biases which could be confounding the outcome. So with switches, most of the time you're switching from a Filgotinib to either UPA or Tofa. And for us it will be Filgotinib to upa. And for partial responders, we have to make a special application in our region to do that, which we do. And obviously if somebody has a side effect, you can switch either way.
Now, if you have a side effect on UPA and you haven't had a response to Oopa, it's probably illogical to try Filgotinib. But if you've had a good response to Oopa and then there's a side effect, there's no reason why you can't go to Filgo. With Filgo you can go switch to Oopa whether it's a side effect or non response.
But generally, again, if they've had a no response at all to Filgotinib, I might not go to Upadecitinib. But certainly if I've had a partial response, I would always try upadisitinib.
[00:48:01] Speaker A: Okay, that's really helpful.
So if we can talk about P19s. I'm not sure how many registration trial data or how much registration trial data you had available at the time of writing the BSG guidelines for Miracizumab, Risankizumab, and certainly, probably, probably not Gazalkumab. But can you tell us a little bit about how These three different agents compare both mechanistically, perhaps in terms of onset of response to Ustekinumab. And how would you, and this is a very difficult question and I appreciate you might not be able to answer it, but how would you position them in the use in ulcerative colitis?
[00:48:43] Speaker B: So that's a very actually difficult question you have just asked. Of all of the questions you have asked, it's the most difficult and I'm going to explain why. So what we wanted to do with the BSG guidelines and we knew they were going to be coming out around the summer of 2025, and bearing in mind this process started in summer of 2022, just shows you how long it takes to develop guidelines, is that we wanted to try to have all of the drugs which were available at the time point that were published. Otherwise, you know, you put all of that hard work in and you feel a little bit silly. If a drug has a nice TA and it's not even mentioned now at the point the guidelines were released, every drug with a nice TA was included.
So we had the induction and maintenance data for Miracuzumab. So we had the whole set.
We only had the induction data for risancuzumab and we had no data for guzulcomab. But equally we also had a feeling that guzulkumab is not going to have a nice TA at the point the guidelines were going to be published.
Okay, now you know, again, can you differentiate between the P19s?
The great certainty of evidence and the magnitude of effects, of course will look different. But I've explained it why. For Miracuzumab we had induction and maintenance and we know P19s have a massive lag effect in placebo.
So this is the worst class of drugs to put into a network meta analysis.
Because when your network meta analysis is dependent on an induction period re randomization, then a maintenance period where most of the placebo patients are actually placebo induction exposed to drug patients with a massive lag effect.
An NMA is not built for specifically a drug like that.
But you know, I'm going to go back to the point we don't have a Bethel methodology and that this doesn't apply to any other class of drug except Ustekinumab, which we also saw a signal where the lag effect in placebo after a placebo patient has been re randomized when the previously had drug is quite high. And this is not just something which we're seeing in IBD with this class of drugs, they've seen it in psoriasis as well and they've seen it in joint clinical trials as well. So we have to appreciate that this drug has a large placebo lag effect which is going to affect the certainty of evidence and the magnitude of effect when you analyze the maintenance cohort of the patients who have been in the trials.
[00:51:19] Speaker A: Okay, and how or where does the BSG guidelines recommend you position.
[00:51:27] Speaker A: IL 1223 or P19s in ulcerative colitis?
[00:51:31] Speaker B: So there's no head to heads in ulcerative colitis between a P19 or between P4T ustekinumab at this time point.
So we aren't able to position in absence of a head to head. And even if you have one head to head, you can't position across the rest of the medications. My own experience with these drugs, they're very nice drugs. P19s and P40s side effects are very, very low.
You know, the interval of the frequency of interval is very good from a patient perspective.
And actually they're all going to be in subcutaneous maintenance, so it's not going to overburden the infusion suite. Kazulkumab is going to be available from a subcut induction pretty much from the go.
So you've got completely ambulatory option. And I'm pretty sure we'll see that for the other two in due course as well. Farzancuzumab and Mirancuzumab. Now the way the trials look is in your patients who have previously not responded to anti TNF, the P9 teams look a little bit better than Ustekinumab.
Okay. But again, this is not from the guidelines. This is from the other evidence which I have seen and the NMA sort of summary of outcomes.
And Ustekinumab in my opinion, if you going to use it, first line is a very, very good drug for ulcerative colitis. Now the reason why I haven't mentioned it earlier in my first line use is that at the moment the nice TA for Ustekinumab is in anti TNF failure patients.
But Astekinumab today is in a unique position. It's a biosimilar. Now it's a very cheap biosimilar. And you know, just going back to the Adalimumab point of view, if you were using Adalimumab from a cost perspective, then maybe today think why not use Astekinumab? It's a marginal gain, okay? But that's what we're dealing with. In IBD we do not have game changing drugs yet.
We're still working towards that. But definitely the data readout for Ustekinumab in bionia naive patient hits the endpoints which we were looking for and cost now is not going to be significantly different to Adalimumab.
[00:53:44] Speaker B: There is no data at the moment to help split between who you should use takinumab for and who you should use P19 on.
The key opinion leaders will always say higher inflammatory burden and there is a signal that if you have a baseline higher inflammatory burden, not only there where you have the option of using a higher dose P19 in maintenance should you take, but probably those are the patients who will do better on a P19 upfront compared to Ustekinumab.
But if you just think of a moderate UC patient, there's no data in my opinion at the moment to differentiate between the drugs. And this is an area where we are going to really have to see and the UK collaborative community hopefully can produce some data on this to see how Ustekinumab failure patients do on a P19. Because the truth is with the difference in prices now, I don't know any part of UK which is going to be able to bypass being a P19.
Yeah, let's be totally honest about this.
The cost pressures are so high that it's going to take a lot to justify using a P19 before before astekinumab with astacinumab bisimilar having also a price reduction within the first year of it being released.
Where at the moment I would favor going for a P19 is for example in acute severe UC patient who has needed cyclosporine who has previously failed infliximab. There I'm quite absolute where the cyclosporine bridge now goes to a P19 before ristakinumab because that's the highest risk phenotype and that patient has the most to lose. So I can justify when I make the application and the ICB will accept the higher inflammatory burden in that context of patient and then obviously if a patient has failed infliximab we try to get them a P19. I'm not going to say it's always possible, but we try to make the application to get them a P19 before ustekinumab.
[00:55:49] Speaker A: Okay, that's really helpful reflections on that group of drugs. And then I guess finally if we come on to vetolizumab, is there anything new that we can take away from the BSG recommendations on how to use vedolizumab in osteocolitis.
[00:56:07] Speaker B: So, of course, vedolizumab was available at the last iteration of the guidelines.
I think only anti TNF and vedelizumab were commented on in the last guidelines with the full readout for registrational studies.
It's amazing how much has changed from 2019 to 2025.
Vedolizumab, of course, has, like all of the drugs, a conditional suggestion, except for upadicitinib, which has a conditional recommendation. I will keep pointing out those nuances so people quote it correctly, but velizumab has a conditional suggestion. You know, in my opinion, for ostive colitis, vedolizumab is a very good drug if you can get access to it. The earlier you can get access to it for a patient, the better.
But it will, of course, come down to local pathways and local access.
There isn't a flavor in the BSG guidelines on this because safety signals in registrational clinical trials look very different, if I'm going to be honest, between most of the drugs which we talk about. But we do feel that vedolizumab, ustekinumab and our P19s are in the safest brackets of drug we have.
So in the higher risk patients, from a safety perspective, it's a go to drug. But equally, I have to be fair to the P19s and ustekinumab, they are also in the same safety bracket for me and we have a lot of experience with that elizumab and we know it works.
We've had vedelizumab for many years, so the statements on vedelizumab have not changed.
[00:57:38] Speaker A: Okay.
[00:57:39] Speaker B: The future for vedelizumab, you know, is looking, from my perspective, quite unique in that. What is new in the guidelines for vedelizumab is that it's got the only trial in pouchitis.
[00:57:51] Speaker A: Yep. So it's now a recommendation there. Yeah.
[00:57:54] Speaker B: There's a good practice statement.
It's not a grade because the trial wasn't big enough to grade, but it's a good practice statement that for pouchitis, this is the only drug which has evidence and then you use your others after then. But of course, local access comes into play here and the new trials which Takeda are doing, where potentially you're optimizing patients with another agent transiently, there's a lot of Alpha 4 Beta 7 going on in the combination world at the moment in clinical trials.
So, you know, I think we will be learning more about vedelizumab in the next 10 years, as we have in the last 10 years in different ways of using it.
But I think for pouchitis locally we can be fair to the clinical trial, which we should do.
It's the only drug which has a randomized control clinical trial in pouchitis. Of course, pouchitis is not strictly uc, but it's a complication of UC if you then had a pouch situation.
And important to point that out and.
[00:58:56] Speaker A: I think also quite important to point out that we're going to learn a lot about targeting treatment or the targets that we set for treatment from the verdict trial, for instance. So fedelizumab will give us some helpful information about that over the next couple of years.
[00:59:14] Speaker B: Yes, and again, you make such a good point statement there because I hadn't thought about the verdict trial, but there's no data at this time point which helps us use four weekly radolizumab from a clinical trial perspective.
So I don't think most regions have access to continuous maintenance of four weekly retilizumab. The other clinical trial did not show a positive P value. The name has escaped me, but the initial clinical trial for dose escalation in UC did not show. But the verdict initial readout which we're seeing is showing targets driven hard targets to achieve could be achieved in a protocolized way and with very meaningful outcomes. And we are hopefully going to see how to do this better with a clinical trial like verdict. The. You know, again, with Vedolizumab, safety is not a concern.
So dose escalation, everyone is happy to do that from a safety perspective. It's just the reimbursement which is an issue at the moment.
But I think the future for vendelizumab we're going to learn a lot about this drug in five years.
[01:00:21] Speaker A: Yeah, for sure. I mean, just the initial readouts from verdict telling us that it is possible to achieve a endoscopic and histological remission in a shorter term and that can be a shorter term target. So that's really helpful and we really look forward to the results from that.
So as we sort of draw everything to a close, how would you then summarize the key findings from the guidelines if you had the to give me a one minute summary of the key recommendations that we should take away for.
[01:00:52] Speaker B: The ulcerative colitis section? I think the first paragraph or the first four paragraphs are the most important and it gives you a approach to how to manage a UC patient. So it starts by saying a UC patient presents, whether they're mild to moderate or moderate to severe. Mild to moderate. You would start with nasalazine plus minus topical mesalazine, moderate to severe. You will probably start with prednisolone with mesalazine and then you do an early response check within two weeks.
And if they're not responding, you escalate to the next treatment. So if this was somebody who was just on mesalazine, you go to steroid. If this was a patient on steroid and mesalazine, you go to an advanced therapy. So the key message in these guidelines for me is that there is no reason now if somebody is flaring to withhold an advanced therapy. And you know, we should not be over utilizing steroids even in the first six months of an individual's diagnosis. So if a patient is on their second course of steroids within six months, we should be starting an advanced therapy.
[01:01:56] Speaker B: After that. My key message is that do not get worried about the nuances, about grade, about the strength of the recommendation, about the certainty of evidence.
All of those drugs which have been suggested or recommended, in my opinion, are okay, you know, if that's the discussion you're having for a moderate to severe patient, should we be giving agent A versus agent B? You know, you're on the right page. Doesn't really matter. It's more important they get one of those.
[01:02:23] Speaker B: With the statement on Adalimumab. I think it's up to individual units. Okay, I get we are in a very cost underprivileged situation in most parts of the country at the moment.
But then you have to be transparent to the patients that. Look, the national guidelines, it has read out like this for these reasons.
Okay? And you know, I think a patient should be aware because it's not nice if they read the guideline to then find out a drug which your national society hasn't recommended is being given to you. But you just have to be transparent as to why your unit is giving it for the unit reasons.
And you then monitor that patient a little bit more closely within the first two to three months. Okay. I should say it's not like. It's not something which I would do, but that's what I would say with Adalimumab. And those are my summary statements. We haven't really touched on acute severe ulcerative colitis, but there's a very nice section there.
Basically it says you can use whatever dose of infliximab you're comfortable with, whether you use standard, whether you use intensified, whether you Use accelerated or whether you use accelerated intensified. There is a little bit on albumin as a prognostic marker in acute severe uc.
[01:03:31] Speaker A: I think there's going to be a whole episode on acute severe ulcerative colitis. So I'm sure they will definitely go into that in detail.
[01:03:39] Speaker B: And there's a nice section on proctitis. Just again, how you go through the treatments and then, you know, just one quick line on the treatments which we have not suggested. So adalimumab is out in terms of not suggested. Methotrexate is not suggested. Antibiotics are not suggested.
Probiotics at the moment is still in the context of clinical trials. So it's not suggested. All of these not suggested drugs, by the way, there's nothing stopping people using them in a clinical trial. Remember, that's a different situation.
And the pouchitis again, I'm just going to give a shout out that we do have our first randomized controlled trial which we were able to mention.
[01:04:17] Speaker A: Okay, that's amazing.
So looking at the future, you do a lot of work with clinical trials.
Where do you see the unmet needs in clinical trial research in advanced therapies and ibd? And what would you like to see from clinical trials? I know one very big aspect was lack of clinical trials in the acute severe UC space and you and your colleagues are fulfilling that. Can you tell us a little bit about Akeso?
[01:04:46] Speaker B: Thank you for that question.
Of course, very close to my heart. So Tim Rain, Seb Shahi and myself, the three national leads for the CASO trial and we are in November 2025 and I think we have recruited over 75 patients which is really good from a UK perspective, but amazing. But although it's amazing, we have to hit our target within. We don't have long. We've got 15 months to get to the sort of 330 patients.
So anyone who is listening to this, please, if your center is doing the study, try to get all of your acute severe UC patients in. I know Krishna, you're doing it as the local registrar who's leading on it. So thank you. Acute severe UC is a research met unneed for many reasons. We don't have a new upfront treatment since really the 1950s. So intravenous steroids is the only approved upfront treatment. Nothing else has actually had a positive clinical trial. There was a nutrition study in India which was really close but was underpowered sadly. But that didn't give a long term solution. It helped with the first seven days where giving IV steroids with Enteral nutrition may enhance the effect of intravenous steroids. But, you know, the real questions in acute severe UC is that is there a drug which you can just give with intravenous steroids upfront from the point of admission, which then not only treats the acute severe episode, but treats the moderate to severe uc, which it then downgrades to, and then hopefully maintains them in the state of normality. So the ACASO trial is looking at upadisitinib. Upfront is the primary endpoint in the clinical trial. And then we also have a sub study for the patients who didn't get upadisitinib upfront where they can get upadisitinib as a rescue therapy.
Now, with JAKS as a class, we have seen a study from India which has used an unapproved dose in Europe of tofacitinib, where upfront there's a positive signal with a positive P value for doing the trial, which we're running, but with tofacitinib at an unapproved dose.
And in India, they're also looking at JAK inhibitors as a rescue treatment.
[01:06:59] Speaker B: And I think they're looking at that in Canada as well. But the protocols going on in the other countries I haven't seen, and certainly they're looking at it in America, as well as JAK inhibitors as rescue therapy. So there is a class of drugs and definitely in the next five years we will have a lot more data on using them as upfront treatment, as well as potentially using them as an alternative rescue option.
[01:07:24] Speaker B: I guess, you know, there still isn't a treatment which has shifted our outcomes to 80% clinical remission within one year.
So in a profile, which is in the Crohn's section of the Crohn's Disease, of the BSG guidelines showed using our oldest treatment in a very different way has given us outcomes which we have never seen before.
You know, it breached 80% primary endpoint, which is incredible when you think that the registrational studies. And again, I'm going to go back to the point, which is why the statements have to be conditional, because even our oldest drugs, we are learning about them.
We had an ASAP clinical trial with infliximab in Australia and we've had a European study as well, looking at targeted levels and dose optimizing based on a dashboard, and neither of the studies, sadly, came positive. This is a very difficult area to do research on. Tim Raine, with other colleagues in Cambridge, also led on a study using Anakinra as an upfront treatment and although that was a negative study in terms of the effect of the cetim, we have been able to learn so much from that study in developing a keso and of course Tim is part of a caso but he's been able to give us so much insight from Ayaso and the sisters. And you know, again it's reflecting in how the uptake of the study has been, you know, so many centers want to do it and we are hopefully we need to hit 100 patients by the end of this year and then the 300 patients by the end of next year. Fingers crossed. And then hopefully the outcome.
[01:09:06] Speaker B: We don't know which way the outcome is going to be.
[01:09:08] Speaker A: No, but I think it's really, really interesting data and especially from ISO, it definitely showed us that we were able to or the CIS were able to deliver a clinical trial in acute severe UC and that to able to deliver it during COVID which is, there's lots of learning from there. So.
[01:09:29] Speaker B: And UK delivered construct and it's one of the largest studies in ibd, let alone the largest ASOC study from number point of view that construct UK delivered, you know, in terms of other aspects, we're looking at how to change the therapeutic ceiling. That's what it comes down to at the moment.
And there are combination studies starting left, right and center. There are going to be more head to head clinical trials because we do need proper, robust data for positioning. But it's going to be very difficult because unless you have multiple interventions, you know, agent A might be better than agent B, but what about agent C D, E, F, G, H, I, N, G, which we have.
So I don't think network meta analyses are going to go away. In fact I'm seeing more published every year in terms of increasing numbers than decreasing numbers and some of them are going into very high quality journals.
I also hope we have personalized medicine, but we are very far from this now.
Profile was the first study in UK which I've been aware of, which was looking at an intervention based on personalized medicine. We don't have any interventional studies at the moment, but we are looking at, there's a lot of studies capturing data at the moment, microbiome, genome, all sorts of markers to try to see are there any signals. Because really when you look at that page of drugs which we have gone through and discussed today, if we had a biomarker which told us for this patient this is the optimal drug and we know this, you know, yesterday we had a meeting at St. George's and I presented a patient who started with mesalazine with uc steroids at first flare, sadly, had steroid psychosis. This is going back to 2017.
[01:11:15] Speaker B: So the steroid psychosis happened in conjunction with azathioprine being initiated at the same time. Then azathioprine maintenance didn't work.
Acute severe admission, infliximab and methotrexate worked for two, three years. Lost response, did not respond to ustekinumab. And then 2022 options were clinical trial or vedolizumab. And she opted for vedelizumab. And then it worked. But it would be so nice for that patient, if we had a. Some form of signature, to have told us up front, Vedolizumab is the best drug for this patient. Yep. And there's. And you wouldn't think normally vedolizumab has a very high chance working when you're using it as your third advanced therapy.
And then she's had a dvt. So that's why we couldn't give her. Well, we chose not to give her a JAK inhibitor. But the personalized medicine predictors need to come in. And then, you know, there's hopefully non advanced immunosuppressive therapies as well, which should be coming through.
So there is a big appendicectomy study which is going to restart, led by centers in Europe, of course, but there will be UK centers. I think we're going to do it. I suspect you guys will do it. Where in conjunction with another treatment, a group of patients will get an appendicectomy and some won't to see if there's a way of optimizing using. Really now, what is a small intervention, half a day case procedure with a rapid recovery.
Yeah. And then combination therapies, I think I've mentioned. But there are going to be a lot of combination therapies being trialed, so.
[01:12:55] Speaker A: Lots to look forward to in the space.
[01:12:58] Speaker B: Yes.
[01:12:59] Speaker A: Okay, so I think we have covered everything that I can think of on the subject of advanced therapies. Is there anything you wanted to add as we finish off?
[01:13:08] Speaker B: Nope. I think that's a comprehensive cover and, you know, in the interest of time, because people aren't going to listen to her podcast over an hour.
[01:13:17] Speaker A: So, yeah, we've definitely done a very thorough. A deep dive. So thank you so much for your time and thank you to the BSG for giving us the opportunity to share our thoughts on the section.
