EULAR 2024 Day 4 Recap Save

Hello, everyone. Thank you for joining us on the ULAR twenty twenty four daily recap. It's the last day of ULAR twenty twenty four, and it's day four here in Vienna. We're gonna go over for you some of the highlights of today. I'm Jack Cush in Dallas, Texas.

I'll let my discussants introduce themselves orally.

Hi. I'm RheumNow. I'm from Glasgow. Nice being with you all.

David? David Lou, Melbourne, Australia, but happily here in Vienna, where it's I mean, this is one of the most beautiful venues for EULA. I I hate to say it to all the other EULA venues, but what a great city.

And today is a really nice day. 76, sunny. I'm looking out at the Danube, which is moving really quite well. It's it really has been nice. What's been great about this meeting, forget the fact that they give us schnitzel at lunch and and yucky and and that sort of thing, is that I don't know about you, but my commute to the convention center is really easy.

I mean, I walk like, I don't know, five minutes and I'm on the metro and it's one stop and then boom, you're there. I'm ready to go. It's amazing.

It's been the best for that. I mean, they just know there's a reason why this is number one in the has been the number one economist on the economist list of most livable cities in the world.

Oh, really?

Yeah. It's never it's just I'd I'd move here if my German was better.

I'm no German and I'd still move here. All right, let's let's begin. Orly, why don't you begin with your favorite from today?

Yeah, absolutely. I I sat in the late breaking abstract session session with great interest and one presentation caught my attention, actually a few of them, but one of them was this PPV06, which is basically a vaccine immunotherapy that is targeting IL-six. What I found extremely interesting is that it's not developed for any inflammatory arthritis. It's been tried at this specific moment in osteoarthritis, which you know have an interesting because if you look back in publications for hand osteoarthritis when they tried tesalizumab and it didn't work. I'm thinking oh that's that's brave.

But anyways it was a first in human. It was 24 patients with neo osteoarthritis. It did not look as efficacy as a primary outcome anyway. So I'm not going to be able to tell you whether it works or not. The idea was to look initially whether it was safe and whether it does work and it does induce antibodies against interleukin six.

So what they looked at was adverse events and there were not particular safety signal there. So they deemed it safe. The other option, the other question was, is it immunogenic? And it is, it does induce anti interleukin six antibody and neutralizing antibodies. And one thing that, you know, we could be concerned about was other and auto active T cells, because that's something we don't want.

And actually there wasn't any. So they're quite happy with that. They did see that there was maybe a trend in reduction of the CUS, but you know, I wouldn't go as far as saying it works. Definitely something to follow-up on maybe at ACR.

How many patients did

they do? The number did I? LBAE0011.

Okay, and how many patients?

24. So very limited sample, first in human.

Good size for a first in human. And, you know, I imagine they did this because of potential effects on cartilage potential of inflammation as intermittent part time, small time, sometimes big time driver of OA early events. Maybe a pain mechanism thrown in. So it might be interesting to see what happens down the line, but certainly novel. What what was the audience reaction to it?

Well, I think, you know, it's it's so early days that that, you know, it's it's hard to get so excited about it. But I think there was also a lot of questions about mechanism of action and why not just trying, you know, tocilizumab, you know, what, you know, what would the advantage of that specific way of targeting IL-six?

Yeah, I mean, I would say from my experience, I've tried lots of intra articular anti cytokine therapies in a lot of different places. And that's never worked for me. Despite my adventurism, therapeutic adventurism. But nonetheless, it's kind of cool. All right, Dave, what do you have?

I just want to say with the last one, I reckon though that the diseases are most irrelevant. I mean, it's quite mechanistically cool. But I think what Christian Diaco, the chair was saying was really relevant. And that you can imagine if you got co administered therapies in Amoxys, you've got a good chance of dampening your immunogenic response. And so I think they chose the most benign, well, inflammatories benign disease that we treat, which is probably, you know, I don't know if osteoarthritis is one, but it's pretty close.

And that was why they chose- But I mean, clearly the benefit is going to come. I could just imagine in the future, imagine if you gave this to someone with PMR, something really IL-six driven, in newly diagnosed patients, and then didn't give them any steroid. I mean, I think that's where you'd love to go. But you can't do that now because we're trying to still figure out whether the thing actually can create an anti IL-six activity.

And then doing healthy controls, right?

Yeah, almost. I mean, that's basically where we're at. Which is why they did put the efficacy outcomes. I mean, this is not what the speaker said. The speaker could ask this directly and just kind of walked around this.

But they put the efficacy outcomes at the end of their of all the discussion, which you haven't seen. You know? I think that's why.

Well, and it may be that they're they're fishing not so much for which disease to use us in just to show that it works. And then who knows where it's going to go after that. So works biologically that is. So interesting nonetheless. All right, let's go to our next one.

So I want to talk about nipocalimab, which is the anti FcRn monoclonal antibody. We saw this at ACR last year in the seropositive rheumatoid arthritis. It did not work there. I feel like that was just testing it in a disease which you have to use. And it did reduce down rheumatoid factor and acupatitis in that population, but didn't really have much of an effect on rheumatoid.

So I guess FCRN, it's at other end of antibodies. You're going to get clearance of antibody complexes. It's, I guess, very simply, I think about it as plasma exchange in a bottle. And it probably that's to some extent, you know, when you start thinking about that, you start thinking about where potentially immune complexes are useful. And we've seen it actually, I think it's already registered.

It's already approved, FDA approved for generalized myasthenia gravis.

Right. Saw Got a few other indications as well. They're they're in play neurologic disorders, especially. So it's being shopped, if you will, into now our diseases.

And that's where we saw Sjogren's, which, you know, I think has been an area where there's been a lot of therapeutic investigation in recent times. And I think that's where it gets interesting that that's where we're going. And certainly, you know, this is- it's- well, it's a positive study. This is looking at a patient population with a high STI. So really, I guess when I think about it simply as a non Sjogren's disease person, I think about it as that systemic inflammatory disease activity.

So not just sicker symptoms. And it does really well on the SDAI. It does seem, I have to say, they showed assimilated slavery production, and it does seem to work on that. SPRE not so much. SPRE is the patient reported outcomes, and we know they're hard to move.

And if you look at the kinetics of it, the trends over time, you have to say, well, the higher dose of nipocalimab did seem to have an effect there, although it tailed back up and that's probably why on the last observation, that's why it didn't- probably why it did wasn't statistically significant. But, you know, I think this speaks to what we're doing in Sjogren's. So I mean, firstly, think the agent is novel, it's cool. I'm sure it's going to find homes in amongst our diseases. Secondly, I think it speaks to what we're doing in Sjogren's.

So we saw daslodalibet, the anti CD40 ligand inhibitor, and someone will tell me if I've got the wrong anti CD40 ligand inhibitor because there's a few of them floating around. But I think what was really cool was looking there at the high STI patients. So you know, just like this high systemic inflammatory disease activity, that's one study. And then as Roy Fleishman pointed out, looking today as a question on the floor, looking at the patients with low SDI, the high SPRE and really sicker symptoms, which I think is probably a lot of what most people think about as Sjogren's when they're in everyday practice. And dasadalimab did do well on those patients.

So I think it'd be really interesting to see nipocalimab in those patients as well, because I think that's where I really need something right now.

So desadalamab is the anti CD4 ligand, right? Yeah. And that was a positive, looked to be a positive study. So And it failed in rheumatoid arthritis, by the I got to wonder, by the way, and I'm anti Sjogren's, I think Sjogren's is a done deal and no therapy has worked in Sjogren's thus far. There are many, many crash and burn failures on the beaches of Iwo Jima and throughout rheumatology and Sjogren's syndrome.

So, and I think there are a lot of reasons for that. And the question is, is there residual inflammation? Now, I agree that there are patients with systemic disease who are significantly at risk for some poor outcomes that are in search of something here. But this is a tough disorder to take on. And it'll be interesting to see if as it goes maybe into another round of trials, whether it might do well.

I'll hope for them. Maybe I'll just pray for them. But I got to wonder, with molecules, especially like this, It's trial and error and trial and error translates to a lot of money and a lot of time. And I got to wonder when is AI going to step in and say your greatest yield is going to be in, know, chronic inflammatory demyelinating polyneuropathy and not MS or, you know, or in myasthenia gravis and not rheumatoid or whatever. And I don't know if those models have yet been built, but AI is certainly going to shorten candidate selection for drug development.

And then also it'll certainly shorten how trials are conducted at great savings of time and expense. I don't know that when you get a candidate molecule like this, it looks like it's immunologically active. Whether ultimately AI can tell us better where we should be starting with and improve the yield over a senior vice president who was first in his class at athletics and last in his class at math. So I don't know. What's the right way to pursue this?

Can I just, I mean, oh, sorry, go? Go, Emily.

Yeah, I knew. I mean, I don't have a massive knowledge of trialing in in Sjogren but I do have some knowledge of trialing in RA and so, one of the thing that we do is that we look in the tissue sometimes and the tissue give you answers and you know sometimes the ways to kind of scan was a drug could be effective in our is is you know you take a biopsy, you give a drug, you take a biopsy again and you look, you know, how the infiltrate those and I wonder if they do that in as well because obviously, they've got access to tissue. So, that that's probably something if it's not looked at yet, it's probably something to look into. But yeah, David's.

There's something in out the pharmacovigilance world called a safety on a chip, where you can actually, you know, look at the safety profile of a drug in development very inexpensively, very rapidly, with wide ranging effects as opposed to, you know, trying to replicate all that in preclinical animal studies and whatnot. So, David, what do you think is going to be the future direction of this kind of development?

Yeah, I mean, just like orally, I think I bring my own biases to this. But I mean, so firstly, I'd say that during COVID and before that, we've had repurposing studies where we basically try and identify the ideal repurposing candidate based on the immunological properties of a given agent. And there is machine learning involved in that. Think it's entirely plausible. You could do it a little bit the other way.

But I think what I've realised over time is the Senior Vice President sitting there making these decisions has to in fairness, I think, is not always going to pick the disease where the drug is going to work the best. Sometimes it's about where the road's already been laid in terms of all, I guess, the infrastructure around that disease process and what the FDA is going to want and outcome measures. Sometimes it's about the available market and of if it's a crowded market, if it's competition or not. And I think sometimes it's probably got a lot to do with commercial realities in terms of marketability in different markets, which I think for us as clinicians is frustrating because we don't need another rheumatoid arthritis drug, well, as many as we've got at least. And then you see drugs like mavorilumab, which probably does work as well as the other biologics and RA, but it stopped development because there are just too many RA drugs, right?

We don't need another one doing the same thing if you're going to bring another RIA drug to market to bring something better. So I think that's probably the calculus, and I think that's incredibly frustrating as a clinician. But I think it's a- if I was a shareholder with these companies, then I get it, I guess.

No reason to disclose that here on the recording. I'm not. I'm not. Okay. All right.

So, my ire was poked today by poster three ninety. This was a British Society of Rheumatology Biologics Register analysis of their patients and the impact of the EMA announcements regarding JAK warnings. So they looked at like thirteen hundred plus patients starting JAK inhibitors prior to May of 'twenty two, specifically looking at how many of those people would have been impacted by the rules set forth by the EMA. And the main rules were age greater than 65, cardiovascular disease risk factors, being a smoker, and having cancer risk of any kind. The bottom line on the abstract was that of all the patients, and it didn't matter which drug they started or that eighty percent were in violation of one of the four major risk factors, that nearly thirty percent had three or more of these risk factors.

And with smoking and cardiovascular disease being the most common of the offenses in those patients. And again, this analysis suggests that most of our RA patients are therefore high risk when it comes to JAK inhibitor use. This is interesting because, it's totally contrary to my belief in my practice and my patients, where I know the risk factors to be based on oral surveillance. Over 65, a smoker, history of MI, okay? Cancer risk is not actually one of the inclusion criteria that was part of oral surveillance.

It was one of the byproducts, right? So it can't be an input criterion. Turns out all the risk factors for cardiovascular disease are risk factors for cancer as well. And that's why it all seems to work. But in my population, that's a minority.

That's like one in six patients at the most, probably more like one in eight. And the vast majority of patients are already on a JAK inhibitor at the time of the announcement. And then I have to have a discussion with them about whether they want to continue the drug that's been working for them or stop because of something that made the newspaper or the TV warnings. So this week we began EULAR. The very first program, the very first important program was the great debate that I was lucky enough to co chair with Doctor.

Kim Lauper. And the two discussants were none other than David Liu and Janet Pope. And they were arguing about something. They were taking polarized views on the JAK inhibitor issue. I'm not sure they even knew which view they were on, but David had the side of saying, basically all these warnings are much ado about nothing and they don't quite pass the pub test was the analogy he used.

And Janet took the view or was assigned the view that these guidelines and recommendations are there for a good reason and that we should pay attention to them. Turns out at the end after they spent several bouts of arguing and presenting their cases, David did sway the audience a little bit, enough to say that he won. And rheumatologists, I must say, are not all that swayed by all this oral surveillance and warning stuff. A few of you are. Turns out other diseases, other disciplines like dermatology are vastly affected.

They're very afraid of all this data. Anyway, David, what do you think of this BSRBR report and the outcome of your debate?

Yeah, well, yeah. So that data from BSRBR and Kimi Hyrek came up to me afterwards. So thank me for putting it in my slides. And so her PhD student was pretty happy about that. Mean, I think those numbers are probably slightly higher than some of the other numbers I've seen from The US, but they were in the lead up to they were really largely before oral surveillance came out.

I think it speaks to how blindsided we were as a community come January 21. And then I guess I don't think a lot of us necessarily even believed what was going on until the ACR in November 21. And then I guess I think our thinking's changed a lot. And the numbers would show that. I showed data as well from The UK, Hall of NHS England prescribing data showing that a lot of those things have tailed off quite a lot, probably before the safety warnings.

But if I'm to be fair outside of the debate, with the safety warnings, I think that's probably something we've seen globally as well. I do think, though, and I think what people we know JAK inhibitors are useful drugs in the right situation. And the world is bigger than just rheumatoid arthritis. I guess one of the key points I want to make is that there's enormous potential for JAK inhibitors outside. And, to be honest, a warning is quite restrictive in terms of how those other indications look.

There's enormous potential with GCA. We saw at this meeting the SELECT GCA data looked pretty good. We know there's stuff in the pipeline for lupus, for myositis. I showed data for PMR and tofacitinib. We know that TOFA is going off patients as well.

So all of these things are kind of in danger for that. And I think in general that we well, I think one other key thing from this was that there's a whole heap of patients in amongst that eighty percent who aren't really at high risk. We saw data from oral surveillance. If you look at oral surveillance subgroups, if you look at the group of patients who had never had a cardiovascular event before but just had high cardiovascular risk but no event, then cardiovascular risk isn't, arguably isn't increased. The point estimate's pretty close to one.

But David, the most shocking thing that data that you showed was The US data where the risks all was there and the rest of the world data where there was no risk. And that was kind of shocking that kind of fed into the Australia versus Canada argument that was in play. Cause it was the North American risk that was that was really the bulk of what became the guidelines and recommendations and the rest of the world not seeing it. So that was pretty funny and a little sobering at the same time. The bottom line I think is that this discussion continues.

And there is concern there, but there's also a lot of confidence there. And putting it to the pub test, real world about what you're dealing with seems to be a very sage recommendation that Doctor. Liu has made. Let's move on to our second round and these ones will be a little quicker. Orly.

Yeah. So we move on from the Jack, We're moving back to the IL 17 word. I was interested in this ISO Kibep presentation. We talked about it at ACR. One of the things that I was quite impressed about in the early phase two back then was some of the really good responses especially in terms of antisitis.

It seems from some reason to have a very very high percentage of patients with antisitis that did really well after treatment and so I was quite keen to see how that went with their phase three. So just from memory, it's not a monoclonal antibody, it's a it's a it's a receptor protein fusion, sorry protein inhibitor. And so it's the study included three forty plus patients. So sixteen weeks they had the twice monthly and the weekly designs and it was against placebo. And well the data when it comes to PASI hundreds ACR 50.

We're looking at forty percent ACR 15, both arms roughly and fifty percent of Pazi hundreds. It looks pretty similar to Ozure IL seventeen really and especially it it does target only I 17 A and you you know we have the bimekizumab now who could be working a bit better on the skin and so on. But I looked specifically at the antisitis data as well because I was quite curious and it doesn't seem to be that great actually. In fact, people with antisitis, even in the placebo group, they had 50% good response, which is quite interesting. But yeah, so that's I was not particularly impressed actually.

Because like you said, the phase two looks so good on antisitis.

It did.

And now this one looks just like every other drug in antisitis.

Exactly. So yeah, I guess that's, that's that.

But it's a, it's a cool name. It's hard to pronounce even harder to write. It's got a very small, molecular weight, the idea, you know, some people thought maybe get better tissue penetration and maybe that's why it was working and but anyway, it's still early in play. It's going to go forward. And the Aisle 17 bus is getting kind of crowded right now.

So, all right. Doctor. Liu.

Yeah, I just wanted to bring attention to a poster, which is POS four eleven It's from Max Yates and colleagues. Max was in our PMR month, Make Room for PMR, which we did October last year. He looked at over 27,000,000 a database of over 27,000,000 patients in England, so they ended up being thirty nine thousand four hundred patients with PMR, and looked at their steroid utilisation over three month periods over the first two years and saw how that compared to what the maximum they should have got by the guidelines was. And I think it's really sobering that even in the first three months, over sixty one percent of people in the first three months are getting more than the steroid guidelines. And this is the kind of number that persists right through, then you get to the eighth three month period at the end of the two years and it's still fifty seven percent.

It's gone down a bit and then come back up a bit. The last thing we need to be doing for PMR patients is giving them more steroid than they're meant to be getting. I think that's just incredibly concerning because we've already got these people who are at risk of steroid toxicity, we're relying on steroid monotherapy as it stands, and then to be giving more on top of what the guidelines say in the first bit when you wouldn't necessarily expect refractory disease especially. And I think the dangerous bit is that there's every now and then there's contention are not that some of these PMI patients should be getting even more steroid than they are, that that might benefit them somehow. And I'm not sure we I definitely don't think we've the data for that right now.

Did Max look at how long they were on steroids in that analysis?

I think there's still stuff that's being worked through, but I mean, there's a lot of patients- I couldn't tell you exactly the percent, but a lot of patients still on it at two years. But I think it's as cross sectional as it stands. But yeah, I mean, we know obviously from previous studies that median time goes right out. This whole two year myth is there's this two year myth about how you're done and dusted with PMI in two years, and I think that's hopefully well and truly been sunk by now.

Yeah. But I think that this UK data that he's come up with is telling us that we're not doing well. And the question is, who's we are not doing well? It the primary care doctors that are getting a little too carried away with steroid use? Because it is the answer to everything.

I did talk to Carl Thurson from Sweden. He had a nice poster on PMR and he said that, you know, in Sweden, you know, the primary care sector is doing ninety plus percent of the diagnosis and treatment of PMR and the rheumatologists are just getting involved in the problematic cases, the ones that they're having difficulty with. When they, but yet when he does his chart reviews of those patients, you know, he's finding that they're spot on in their diagnosis and management, I think he said two thirds of the time. So it's encouraging in some ways, but then you hear this kind of data and you wonder, well, we certainly are going to need more education on this. The good news is that this area of PMR and GCA has become a little bit of a hotbed.

And that is going to drive new drug development, more education, more money into this system that will I think benefit patients and clinicians equally. But we're going to have to take responsibility for a lot of education. I'd be I want I you know, he's a very thoughtful guy. I'd like to know what's the next step on that because you know, he could probably take that to the NHS and say we're going to develop a program around that and see how that's going to affect patients in care. Who knows?

Yeah. I

mean, yeah, I think it it'd be there's obviously it is a lot of innovation in this space. And I mean, on one side, yes, we love new drugs. But I think on the second side, we just need to figure out how to do all of these things better within the system that we've got at the moment. It's a heap of PMR patients. I don't think rheumatologists will be able to see every single PMR patient.

And actually, another friend of RheumNow, Eric Madison, wrote an article a recent tutorial with and I'm going to someone will tell me if I'm wrong, if it was Daryl Camillino who wrote it with him about the dark side of the moon for PMR. So we seem to study the PMR patients we have access to, and there's all these other patients, PMR patients out there in the community that we don't necessarily seem to be able to understand. And I suspect that's probably where we're worried that quite a lot of harm has happened.

Yeah. Orly, what's a PMR like in your world? How much of it do you see and how selective are you about it?

Yeah, no, exactly. I mean, fully agree with what both of you were saying. I think there's a lot. This first of all, there's massive regional differences in how, you know, is it the rheumatologist? Is it the GP?

Is it who gives the initial prescription? See back in France when I was seeing I was seeing a lot of PMR people in my clinics. And I was giving them this like super super long prescription telling them exactly you know you need to reduce by this and that and by this stage you need to be at this dose and so on and then you see them six months later and they're still at the same dose, you know, they haven't dropped anything and you're like, what happened? And they're like, well, I fell a bit off pain when I went down to nine milligrams. I went back up.

You know, and I'm not blaming anyone. I think, you know, it's human and I get that and I feel like a lot of the and then and then there's those you never see because you know, as you guys were saying, they just didn't, you know, money is already GP and they and they do their own thing and then and then and then in in the in The UK, I think a lot a lot more handled by the GP than in France. So I think it's really tricky. There's a lot of layers to address to that, and I think there's unfortunately not going to be an easy fix.

Now steroids and PMR, I can say two things. One, I like Artie Cavanaugh's blog on playing steroid poker. You know, we all have our own little, I'll raise you this kind of thing. And my version is the steroid dance or steroid cha cha cha. We all do it a little bit differently.

But still the best line came up during our PMR, make room for PMR campaign last October where Steve Paget came up with the line giving steroids to PMR is like giving spinach to Popeye. And that's a little worrisome. So I'll end with a very short but I think informative poster, POS0436 from Mika Haase's group in The Netherlands. It's a comparison of two different cohorts from two different years. One is the para cohort from several years ago, February, RA patients wanting get pregnant.

And the second is a more recent pre Cara cohort, two fifteen patients. The difference between these cohorts is that in an earlier time, we didn't have many rules about preconception and drugs during pregnancy and whatnot. And this pre Cara group is operating under the guidance of retreat to target strategy. And the differences between these groups are that the para group, the older group has at inception a very high dash 28, 3.8. The newer group has a much lower at 2.3.

The para group with no rules, they were more likely to be on no meds and if they were on meds, more steroids, more nonsteroidals. The pre Cara group, the newer one, the treat to target one, more likely to be on TNF inhibitors preconception. And the bottom line is how did they do when it came to finally getting pregnant? And that's called TTP, time to pregnancy. And it was one hundred and ninety six days as a mean in the para group, the older group, the no rules group.

And it was much shorter, eighty four days in the pre care group. The point being that treat to target leads to TTP, time to pregnancy in patients who wish to get pregnant. So a tight control aiming for remission prior to pregnancy works not only in lupus also in RA. Pretty simple state take home message. Did either of you see the UR recommendations on pregnancy lactation and counseling that was presented today?

And I think it kind of cleared the TNF inhibitors for good, you know, and I think that's for the best, you know, especially when you see the data that you just presented. Looks fairly obvious that you need better control the disease to better the fasting and be pregnant and probably the better the pregnancy outcome as well. So I think it's a great thing.

Yeah, it was a good session. I did a video on it. I think you will be hearing a lot about these. You are now not just points to consider, they're to be called recommendations going forward. I want to thank my friends and colleagues for the great discussion.

Tune in to RheumNow next week, we got a lot more coming in the way of videos, tweets, and articles, and more panel discussions. Next week, we're going be live streaming panels on rheumatoid arthritis, systemic lupus, and psoriatic arthritis. I hope you'll be there. Folks, thank you very much for being here.

Thank you.

Alright. Thanks, everyone.