EULAR 2024 Psoriatic Arthritis Topic Panel Save
Moderated by Dr. Jack Cush and Featuring Drs. Eric Ruderman, Antoni Chan, and Peter Nash
Transcription
Hello, everyone. Welcome to RheumNow's panel on psoriatic arthritis from ULA twenty twenty four. I'm joined by the experts who are covering the psoriatic arthritis content at the meeting. In this panel discussion, we'll review for you our favorites from the meeting and get input from our colleagues on our thoughts and impressions. I'm Jack Cush in Dallas, Texas.
I'm joined by my friends who will let them introduce themselves, Eric.
Eric Gruderman from, Northwestern in Chicago, Illinois.
And Peter.
Peter Nash from, downtown, beautiful Downtown Brisbane in Queensland and Australia, but not quite there at the moment, Jack.
Always making your way back home. And Anthony.
Hello. I'm Anthony Chan from, London United Kingdom.
Excellent. Alright, folks. Let's let's begin with Anthony. And what what did you like as your first choice?
Yep. First is the late breaking abstract, zero zero two from McGonagall and colleagues. This is a study looking at five different classes of biologics in PSA. The PRO SPIRIT study with 1,000 over patients they were gonna look, they looked at twenty four months of the efficacy of the different agents. The TNF, IL1223, IL23, IL17 and JAK inhibitors.
In summary, over the period of time, we found that the IL-seventeen namely execizumab was as effective as TNF and JAK, but there were some differences. The treatment with a execizumab brought on a faster improvement compared to IL-twenty three and also the IL-twelve twenty three in terms of the CDAPS score and also in terms of skin in terms of the body surface area this was better than the TNF. This is quite contrasting to another study which was also presented early in the conference the OP0010 from the TriNetX study where they looked at people very early in psoriasis where before they actually developed psoriatic arthritis in that group it seems that the IL-twelve 23 was better than TNF and IL-seventeen. So I think these two studies perhaps tell us about the continuum between psoriasis to psoriatic arthritis and latent disease that perhaps IL-twelve twenty three or IL-twenty three inhibitors could be operating earlier in the disease in terms of the cytokine signaling and later on the disease it seems like IL-seventeen TNF would be more effective. So I thought that was quite interesting, the LDA-two.
So controversial, isn't it? Eric, what do you think about this data and where is its real utility?
Yeah. So let me follow on with one other abstract and then talk about it. And I think on top of the sarah like a map that Anthony just talked about. The other interesting late breaking abstract was the one on molecule called the zocobep, which is not technically a nanobody, but it is another small protein targeting interleukin 17. In this case, just interleukin 17A and not A and F as the nanobody that they had talked about was.
This was a phase 2b and three study. They'd done some phase two work before. It was a multicenter trial that looked at a couple of different doses of this is ozocobab molecule versus placebo and showed that it was quite effective with ACR 50 response rates at sixteen weeks of about forty percent in both arms, and an MDA response that was also about 40% in both arms. An effective drug with also great skin response at about 50% PASI 100s. So it behaved a lot like an IL-seventeen inhibitor.
And I think the interesting question is whether these sort of smaller protein IL-seventeen inhibitors are going be any different than the antibodies that we've been using for some time, ixekizumab or secukinumab. With respect to the, TriNetX, stuff that Anthony referred to, I actually will want to sort of push back on that one a little bit. I looked at that with some colleagues who know an awful lot more about epidemiology than I do. And the challenge with that particular database is that the data analysis isn't great. It isn't, carefully done.
It's a really interesting, system where you can They sort of layer a dashboard on an existing database that pulls data from multiple EHRs, but it's not really well, structured. And it, I don't know how well you can trust the data that's in there because it doesn't really control very well, for confounders and especially confounding by indication when people select drugs, because you're at the mercy of whatever drug that people are put on. So I would be a little cautious about using that to say that one pathway is better than the other. What we don't have in psoriatic arthritis and we desperately need our, head to head studies comparing some of these newer targets, 17 and IL twenty three. We've had a couple of head to head studies comparing IL seventeen versus TNF inhibitors that both show the same thing that they're equivalent for joints, but IL-17s inhibition is better for skin, but we don't have any studies with the newer agents.
They have them in derm, they've done them in derm, so we know it can be done. They just haven't been done in rheumatology.
So can I Yeah? Here you a few comments in there? So I think the the Ezocobet nanobody, they presented three different new IL-seventy inhibitors at this meeting, and they're all very much ho sixty forty twenty, ACR twenty fifty seventy, and they're all 40% MDA. So that'll make a total of what sticks we're gonna have now. So I would not I'm asking the question, how many r seventy inhibitors do we need?
And if you're not ten, twenty, 30% better, what's the point? I get that we need more than one in case someone has an allergic reaction as you occasionally see skin reaction, sec, kinemab, etcetera, etcetera. But how many? And I was just a little disappointed in these new nanobodies that are supposed to have increased absorption and get into tissue better that they weren't actually getting better responses. And with the TriNetX thing, I hear what you're saying.
They tried to do propensity score. They tried to match for lots of different things. And what was overwhelming was the starve. They had 200,000,000 people and pulled out a million PSOs and a couple of 100,000 PSAs. And everything Eric is saying is a 100% correct.
You you know, garbage in, garbage out. And, really, they just showed that there was a difference in the reduction of the ICD code change from PSO to PSA with one biologic a little bit better than the other biologic. And it happened to turn out to be similar to a previous Thingler paper that said the same thing. But, I think if if there's any way that that can be checked for accuracy, the sheer size of it's pretty overwhelming.
So isn't the on one hand we have the data about what works, what's more effective, what you know you might want to hang and nothing is overwhelming us there. But on the other hand, Trinetix was attempting to answer the question, is psoriasis preclinical psoriatic arthritis? And can the evolution of disease to another twenty, thirty percent who develop PSA be altered by more aggressive biologic therapy? There's been reports in the past that are faulted for challenge bias, right? And there's no strong, strong proof that aggressive treatment of psoriasis will stop the progression to PSA.
So where are we in thinking on this issue? It is
Well, that's it's gotta be it's gotta be prospective studies, Jack. And they're doing it, but with a conversion rate of three percent a year, PSA to PSA, you don't have to follow a lot of people for a long time to answer that question. Don't you think, Eric?
Yeah. I think that's exactly the problem, Peter, is that I the these sort of retrospective looks, there's just too many confounding factors involved to really know for sure. You know, the the challenge with the TriNet database, I I I'm not an epidemiologist, but talking to some friends who did you know, the challenge with the propensity score matching, Peter, is that you can't actually get under the hood with that system. You actually literally click a button that says, please propensity score match, and then it does it. And you really don't know what it's matching for.
And so a lot of numbers
They listed they listed in the presentation. You know?
I understand this. But but the thing is that as you said, garbage and garbage. I mean, more numbers doesn't make it better if the data you're using isn't good in the first place. It just sends you down a rabbit hole. But you're absolutely right.
It has to be done prospectively because, you know, you need to take a large, you know, well characterized cohort of psoriasis patients who clearly have no arthritis or early in disease and follow them out for some period of time and see how many and on what drugs get arthritis. But that's gonna take a really long time. As you do that, you can look for factors, whether they're genetic factors or other biomarkers that may help you predict that, but you need the clinical outcomes to order in order to understand whether any of those matter. And to try to do it retrospectively, people were trying to do this for years and it's too complicated because you have no control over what they received. If I have a patient who has psoriasis and didn't get psoriatic arthritis, is that because they never were going to or because of the medication that was being used to treat their psoriasis?
And I don't know that.
All right, final word on these abstracts. Anthony, you brought it up, you have any final comments?
Yeah, think a very interesting concept of this progression from a PSO to PSA. We do know about risk factors, it'd be worthwhile studying the high risk group people and there was another abstract on high CRP being a predictor of future development of PSA as well. So simple biomarkers but then studying in a head to head comparison would be the best way.
Okay, interesting concept. Eric, what's your, one of your favorites?
I mean, I did think that the small molecule IL-seventeen inhibitors were interesting. The other one that's interesting that I think we don't know where we're going with it yet was an abstract on another TYK2 inhibitor. There's another, so we know that ducravacitinib has been working its way through. It's been approved at least in The US for psoriasis and the sort of claim to fame, if you will, these TYK2 inhibitors is twofold, that the way you can inhibit them is more specific that even though TYK2 is essentially the fourth member of the JAK family, its mechanism is such that you can target it more specifically than you can with any of the other JAK family members is you don't have some spillover. And the problem with JAK inhibitors, as we all know, is sort of off target effects and whether some of these cardiovascular and hematologic issues are related to the efficacy of the drug or other effects that you're not hoping to get.
And the TYK2 inhibitors may kind of get around that. The other issue is the TYK2 inhibitor that IL-twenty three signals through tick two. So the idea is you're targeting a pathway that we know is effective in psoriatic arthritis. You know, it's not as good though. Interesting enough.
Sudacravacitinib is, know, in the data that's out there doesn't look at least for skin as good as the IL-twenty three specific antibodies. So even though it's the same pathway, it probably doesn't block the pathway to the same degree. There's enough that gets past it. This new drug now called Zazocitinib, which I love because I think that's the best generic name for a drug that I've heard in a long time. It's Zaz.
The drug? Takeda drug?
Yeah, Zazo, Sydenham. So they presented some early data and the thought there is that it's higher binding affinity and higher potentially, therefore you can drive the efficacy higher, we're given a higher relative dose and still maintaining specificity. But honestly, it didn't look a lot much different than the ducravacitinib data. So we'll have to wait and see. And we don't have a lot of data in psoriatic arthritis yet.
It's all in skin. But they all carry nice, safety profiles with them. So that's a plus. And don't know that these are going to be drugs for people with the most severe surrogate arthritis or the most severe psoriasis, but for people with sort of modest disease, oral drug that has very few tolerability issues and not a lot of safety concerns is potential win.
Okay, anybody have a comment on the addition of the new tick inhibitor?
I think we we're stuck in our country that we have to use two conventional synthetics over twelve to twenty four weeks before anybody can get access to a biologic that's reimbursed. The methotrexate has to be one, and we're mucking around with leflunomide and sulfasalazine as the others. And we'd much rather use Dukra or even Apremolux, which Right. Was not has yet to be approved for PSA in our country because the government considered it wasn't effective enough at its cost to hold people up getting to better treatment. So I'd love to see Juukka as the second agent we have to try before you go to a biologic unless there's very bad prognostic features.
We have a Preliminary S. Don't worry. You're not missing out on too much, Peter.
It is the best selling of all the newer drugs because of its safety profile and derm seems to like it quite a bit.
Yeah, I love it because you don't have to monitor anything. You don't have to check labs. You don't have to follow anything. You can just, as long as they don't have diarrhea, you send them on their way.
Doctor. Shannon, how do you
really good safety profile for some of these agents and I think early in disease where perhaps the disease is not as severe in the mild to moderate cases a lot of these drugs like Premalas, Thick two I think would be probably where we would start them first before they went on to other drugs because of the ease of convenience of taking it. The binding story, the tighter binding we've had this in the other areas IL-seventeen with ICSI and with the nanobodies yeah you know I think only time will tell whether that's going to make any clinical difference. Early data doesn't suggest that it makes a huge difference in terms of the clinical efficacy.
So is the psoriatic space shaping up to be a battle of the highs and lows, meaning that there's entry drugs that people are going to argue about, which always now has to include methotrexate, but in The United States at least it's going to include opimulast and maybe as the TYK2s get into play and also the JAKs, are they going to be lower end considerations? Then if you have more serious skin and serious joint that you're going to be looking at the biologics, especially the, you know, the seventeens, the dual seventeens, the 20 threes, the twelve twenty threes. Is is there this polarized approach or no?
I think for the for the first time, we get individualized choice depending what domain you've got. And, Alexis showed nicely that, you know, most people have three or four domains involved. And the majority have two, three, four. So if you're axial, you've got an individual choice. If you're skin, you've got an individual choice.
If you're if you're polyarthritis, you can individualize your choice. If you got uveitis, IBD, individualize your choice. So I think the real question is, are we wedded to this methotrexate forever just because of history and just because of safety. If your wife got acute psoriatic arthritis with many joints and some skin, would you start her on methotrexate, or would you go straight for one of the very safe semenines or 20 threes? For example, in Germany, they tell me the derms are allowed to go straight to secukinumab not based on evidence, but based on a court case that they were successful in winning.
The patient, that is. So, you know, my son has a PSA, and he's certainly on one of the newer drugs to control his disease at a young age. So I'm just asking you the question. Are we wedded to methotrexate forever when there are agents that many people think are more effective, less associated with nuisance side effects, maybe more suitable in the long, long term, especially young people who like to drink alcohol in Australia. And what should the first be depending on what your domain involvement is?
Is it not the individualized part is individualized to the prescriber and what I believe, as you're suggesting, Peter? Because the guidelines and rapid guidelines levels the playing field on a lot of these choices because they're really the trial designs proving the point. I get it, I the problem was compounded by the PSA seam study, which showed the efficacy of methotrexate and put it back into play when many of us were trying to move away from methotrexate. Maybe not a safe drug in a psoriatic population, and maybe it's certainly not as good as some of the newer drugs versus what we're seeing, but that study kind of, changed
the I think we gotta get away from it, Jack, though. I mean, why are we using methotrexate? We're using methotrexate because it's been around for forty years. Mean, there's a lot
of stuff
for me that's been around for forty years that we don't use anymore because, things have moved on. And just because it's old doesn't mean it's better. I mean, I would challenge anyone to say that the safety profile of methotrexate is better than the safety profile of any of the biologics we're using, let alone the IL-twenty three inhibitors. And the real reason we're doing that is cost. And that may begin to change.
I think, you know, we're starting you guys in in in The UK and in in Australia way ahead of us on this in terms of biosimilars, but we're starting to see it here. So, you know, when you've got access to a biosimilar version of adalimumab, why do you do methotrexate then? How much money are you really gonna save by putting on methotrexate and monitoring, their their labs and having to do a liver ultrasound on some percentage of them because the LFTs are high? I think we need to get out of that and get away from that.
If you have million people with psoriatic arthritis, do you start them off with a $80,000 a year drug or with an $8 a year drug?
But it's not 80,000, it's a $10,000 a year drug. If you're using a biosimilar and methotrexate is not $8 a year anymore. My patients are paying a couple $100 a month. You know, if you just look at the actual numbers, methotrexate is a 2 or $3,000 drug plus all the lab work you're doing, plus the potential, you know, other workup that happens when you see hepatotoxicity. I don't think it's that much cheaper than the biosimilar atalimumab.
And I think we're going to see even more this whole issue of costs in another year, year and a half or whatever it is when tofacitinib goes generic, because all of a sudden, all of the noise about not using JAK inhibitors may go out the window when it's actually one of the cheaper options.
You know, I think
Doctor Chan can correct this.
Right.
Isn't a biosimilar atom, Alamemiumab cheaper in The UK than methotrexate?
It's cheaper than the subcutaneous not the oral one. So I think this is changing. I mean there's a lot of this is down to you know what the payers are saying. So and we don't actually have a lot of evidence in the use of methotrexate in PSA interestingly. But historically we've always been using it.
But as you say the price is coming down and it is likely that, we will be moving away towards using more biosimilars early on in disease.
Okay. Alright. Peter, give us something a little less controversial.
Well, I was gonna give you I I knew you'd ask, so I thought about the themes, and the themes I found six. New r 17 that you've mentioned, telemonitoring. I think you know about what I feel about never examining patients ever again and missing pathology outside of joints no matter how good the the patients feel about it. This prevention of PSA, the PSA we've already talked about. Biomarkers was a big theme.
But there was a GRAPA symposium, and there's a a presentation on this difficult to treat PSA. And what I liked about it is that they'd hived off complex to manage from difficult to treat. And I think that's an important distinction. And it even comes over to the AXPAS space where one of the new ASAS guidelines is if people aren't responding, reassess the diagnosis rather than cycling forever through expensive biologics. So I think there's parallels.
And the D to T definition, I think they're gonna end up with, is fail one conventional and fail two biologics of a different MOA. And then you've got this label difficult to treat, which has to be reworded as treatment refractory or the patients aren't gonna be happy. And so I'm not a difficult person. What are you saying to me? So, anyway, I think it's a it's an interesting initiative.
Complex to manage means a lot of nonmusculoskeletal pain that has to be managed equally as well, whether it's cannabis, whether it's progabalin, whether it's amitriptyline, whether it's diet and physio and the the GLP one drugs, we can't ignore that, and it's just as important. And the implication is if you're can identify the D to T before they've already failed two biologics, Maybe combination therapy needs to be tested, etcetera, etcetera. So I think the whole movement is only gonna be relevant if it changes management at the people we know are going to end up bad prognosis. So I thought that was an interesting, area that's sort of a hot topic at the moment awaiting definition. And the other one that I was gonna mention was the GO LAPSIS study where, again, asking the question, is a TNF plus methotrexate and some steroid any better than methotrexate and steroid alone?
And I must say, was so disappointed in this study that they wasted this fantastic opportunity by filling all the patients up with injected steroid at baseline. So you only had to have two swollen joints and one enthesus to get in. 40 in each arm, pretty small. Took them years to recruit as it was. Early, early untreated PSA.
And they gave him a hundred and twenty milligrams of injected steroid each arm at the beginning of the trial when they started the methotrexate on one side and the galimumab methotrexate on the other, then they repeated another hundred and twenty eight weeks later. And the the group without the TNF got twice as much steroid as the group that were on the TNF, and then they say there's no difference in between the two down the line. Who's surprised? What a waste of a fantastic opportunity to see if starting the TNF on day one would make a difference. Because that was the that was the conclusion that they couldn't show significant difference.
But when you looked at it, there's a big difference in steroid. The numbers were small, and there was even sort of trends like to separate them even given all that stuff. So, I was a bit disappointed in that study because it didn't answer the questions we wanted to answer. For the higher responses like ACR 70, there was clearly a difference that was significant. But even at week twelve and twenty four with the TNF added, MDA was pretty equal across the board.
So missed opportunity as far as I can see.
Let's go back to the the distinction of difficult to treat and complex to manage disease. Anthony and Eric, what does that do for you in the future management of psoriatic disease? Anthony?
I think it's, the important point here is to revisit the diagnosis. And I think the difficult to treat, patients often we have to take into consideration the comorbidities. So a lot of these patients, we are using scores that might be measuring fibromyalgia or there might be an effect of obesity or smoking. So rather than cycling through biologics one has to kind of take into account some of the not only extras musculoskeletal manifestations but comorbidities as well. And so making the distinction between complex and difficult to treat is quite important.
Eric?
Yeah, I mean, think that's huge because there are two different issues, right? The question is whether you have a disease process, that's not responding to what you're treating them with, whether it's a biologic or a combination of biologics or a different biologic, or is there something else at play that's not going to respond to whatever you change them to. And I, and I'm, as I've sort of to compare, as I've looked out there, I'm a little disappointed in what's happening in the rheumatoid arthritis space, because they're kind of muddying the two together. And, you know, I can't speak for Anthony and Peter, but I I'm not infrequently see a patient who's coming in for another opinion who's failed, you know, three or four or five drugs. And the first question I always ask, and I tell my fellows to ask is, are they actually treating the right thing?
Is this really, you know, is this, if they've not found the drug that's going to work on their disease or is this central pain or something else that no drug is going to work on. And I liked the approach that, the folks at grapple are taking in psoriatic arthritis, because they're really trying to separate those two out And that the complex to manage, includes fibromyalgia kind of central pain includes people with osteoarthritis. It's not, I mean, those are not going to respond to a different biologic, no matter what, or a different pathway of biologics. And if we're going to start looking at approaches to these folks, we need to make sure we have a sort of a coherent, consistent pool of patients who are at least potentially likely to respond to whatever we're going to try. So I do like this approach and I think it does have, legs and they're still trying to sort out, you know, as Peter said, you know, how many drugs do you have to fail and what makes that call.
And that's, that's sort of the, the sort of fine tuning, but the big idea of separating out difficult to treat, you know, inflammatory disease versus complex to manage that takes in all the other pieces that we're dealing with is is huge.
You know
And I left out one key point. Sorry, Jack. I left out that the definition of difficult to treat includes imaging evidence of inflammation, whether it's ultrasound or MRI, but not labs. So that is what Eric's saying. You have to have evidence of active inflammation to be d to t.
Yeah.
So the hard and expensive to treat just got more expensive by throwing in an RN ultrasound. Yeah. I don't know that that's an advantage. I think you can hang your hat on other ways of assessing inflammation, but the one you don't want is empiric trials to see if an anti inflammatory agent is going to benefit those who are not responding. So I'm a little concerned about the clinical trials that we've seen in the past showing poor survival of expensive therapies, biologics and targeted synthetics, in both psoriasis and psoriatic arthritis, such that when you look at three years of therapy, less than half the people are taking the drugs.
I want to know from our experts here, is that because these are the D2T patients or is it because we just have too many options for treatment and people are switching off because they can't? Anybody have a strong opinion on that?
I do. I think in a lot of it's the latter. We've talked about this in our psoriatic arthritis clinic. I work with a dermatologist and we've been talking about this lately as we see people. And the first thing is that the idea that two, three years out, seventy percent of people are off the drug eustardom.
That doesn't feel right. I mean, that's just not been my perception, but it is what it is. They're getting that data. But at least in The U S what I'm seeing is I think a lot of it is expectation that we've got so many drugs and so many good drugs that patients are getting to the point that they're expecting to be all better. And I have people come in and say, you know, this is working well for me, but I've got this one little piece of psoriasis on my elbow, or, you know, this knuckle is hurting me a little bit.
And I try my best to talk them down and say, look, you know, you're not a 100%, but boy, you're 95%. And I don't know how much we're going to gain by starting all over and switching to a new drug and you may be worse. And, but I think people are, especially in the skin side that these drugs have become working so well. People see the promise and they're like, why can't I be clear? Let's get me there and let's switch to something else.
I'm not happy where I am. And I don't know that everybody, that we can expect every patient to be 100% controlled. I just don't know that that's the right target.
Yeah, think the drop off is mainly because it's such an heterogeneous condition and we are treating different domains at different time points early onset, late onset, you know, polyarticular, spinal and what's really important is the assessment of these patients after you before and after treatment to ensure that we've got the right kind of phenotype of these patients and hopefully we will be able to then select you know the right agent at the moment very much clinical but hopefully with the future development of biomarkers we hope we'll be able to choose we become victim of choice that we stop sometimes stop assessing people because we know that hey there's another one we can go to and then we get into this cycle. And this is what we need to be we go back to the clinical examine them check make sure it's firstly psoriatic arthritis not osteoarthritis and then what particular domain is it mTCs, you know, we have to just use that a bit better.
Peter, will we do better if we treat by domain and make it personal as you suggest?
Well, I I do what Eric does. I tell him, like, we have to squeeze every last drop out of each agent before we swap and change, because, firstly, it's been very hard to get it, get access, and then, you know, you gotta make sure that that nonresponse is really something to do with nonresponse to that therapy. But I do think the PSA patients are different to RA, and the numbers prove it that they churn much at a higher rate than, than the RA patients. And I wonder if it's because we often treat late, not early. And I wonder if it's to do with choice.
And I wonder if it's to do with flares from intercurrent infection and a million other stress life stress events that makes it just as difficult to treat PSA and that there's a it's a combination of disease almost getting resistant to what you've used and, churn because you have choice and churn because you have flares and things. So it's difficult. There's no easy answer to why they churn. They always have a high placebo response rate anyway in all the clinical trials compared to RA, and they churn more than the RA patients do for some reason.
I want to ask our panel we kind of went over the sotoluikumab, the dual AF inhibitor vial 17, kind of quickly and this along with bimekizumab on the precipice of maybe being approved in PSA. Is there any belief from the data that we have that these drugs are going to be better arthritis wise? We know they're going to be very good skin walks, right? The head to head trials and psoriasis show that, but are there going to be any better arthritis wise and or any safer in in do anybody have an opinion about this?
Well, I think they're gonna end up the cemidines in many countries like NICE in The UK are gonna make people use a TNF first. And the TNFIR numbers with bimekizumab is pretty impressive. And I got a feeling that in many countries, it'll slot into that position not because of what people want, but because the regulators will insist. So at least to be able to say we've got the best TNFIR numbers in any study, but it's hard pressed to show a difference that blocking f makes compared to just blocking a by itself. And the downside seemed to be a little bit more fungus.
I certainly don't think there's any more IBD, but I'd be interested in the other panelists' just thoughts on that.
I think we select carefully so this is why we probably don't have many people with IBD who will be put on to this treatment. But in terms of the nanobodies, it's too early to say, from what we know. Certainly at twelve weeks it looks impressive in terms of its ACR 50 response. Whether you will fall into DNF IR, it probably will be where we practice currently because of the costs.
Yeah, I don't think it's more effective than the existing IL-seventeen inhibitors. I mean, the problem is we have no comparative data, but if you look at their two phase three trials, they don't really don't from the joint side, they don't really look very much different than execizumab or secukinumab. I mean, Peter's right. You know, the one sort of thing they might hang their head on is that it seemed to perform a bit better than the TNF IRs, but that's a different trial than the TNF IRs that were in the execizumab trial or in secukinumab trials. And I'm a little bit cautious about sort of making too much of that.
And I'm also not sure that inhibiting IL-17F that there's some mechanism why it should work better though. So, I mean, there's no rationale for why it should be better in TNFIR necessarily, you know, that, that the problem, the promise of IL-17F inhibition is really for skin and it works there. It's a very potent drug in skin. But I don't think there's a heck of a lot of difference if any on the joints 17, and that's no different than the other two we already have.
Okay. Do we anybody have any last ones you wanted to get in before we conclude our panel?
Yeah, if I got one it's a more info spa this time if I can share the oral presentation one three two. This was a treat to target approach in SPA which I thought was interesting. It's people very early disease one year disease duration and they put them on galimumab versus anti inflammatories once they got onto remission they came off the treatment but very quickly 84 of them flare but the time to flare was a bit longer in the golimumab group one hundred and fifty five days versus the NSAID group which was sixty one. What it showed is that the male patients low best die and non smokers were the people who are more likely to get into remission. So I thought it was interesting to study this early in disease most of our studies are eight, nine years of disease duration.
And Jack's already mentioned, sorry. Eric's already mentioned the the JAK inhibitors. Well, the Chinese presented AS data and PSA data of a JAK oh, sorry. RA data of a JAK their own JAK one inhibitor, which looks and tastes and smells and feels like a JAK one inhibitor and has results that are unbelievably good. And the safety profile that's also unbelievably good.
The higher dose didn't have any anemia, and the and in fact, they don't show any zoster results. So when you ask them, yes, they had a couple of cases. So we need those molecules out multinational studies, but they'll be quite happy to do them in China and not, see the rest of the world. They've got a big enough patient population. But Eric's right about, TOFA.
They tell me there's eight generic TOFAs in Buenos Aires.
Mhmm. Yeah.
My understanding in India right now is that, generic JAK inhibitor is the drug of choice for RA at this point because it's incredibly cheap. There's a million generic options.
And then I've actually seen a a publication where they compared the generic TOFA against the, originator TOFA and like a biosimilar type study, and that was equally as effective and had the same profile.
Perfect. At the conclusion of meeting, didn't GRAPA Habits meeting at UR, Eric?
They had their meeting beforehand, and I don't recall if there was anything dramatic that came over. They have a number of projects that they're working on, both educational and this whole idea of defining the difficult to treat patient really as a pathway to then doing some clinical trials of that population to really understand the best treatment approach.
So it's a project. Sorry, it's a big project on gender and why there should be differences in baseline disease activity and responsive therapy What's gender? Females.
What blocks? I don't know what you're talking about. Gender?
Pardon?
Gender.
Sorry. Gender. So females have high based on disease activity respond less well. Okay. There's a very giant project underway to work out why that should be and whether we should stratify all clinical trials going forward for gender.
Right. There's a big biomarkers collaboration called Hippocrates. There's a big combination study underway with GRAPA, combo 17 no. Combo twenty three t n f versus 23 alone. But there's there's a number of things underway that are trying to answer some of the issues that you've raised, Jack.
Okay. Alright, folks. This has been a a lively discussion. We appreciate your oversight and review and your careful attendance at all these sessions and and educating us on what's happening in psoriatic arthritis. Have a good evening.
Alright. Thanks
a lot. Thanks. Take care.
I'm joined by my friends who will let them introduce themselves, Eric.
Eric Gruderman from, Northwestern in Chicago, Illinois.
And Peter.
Peter Nash from, downtown, beautiful Downtown Brisbane in Queensland and Australia, but not quite there at the moment, Jack.
Always making your way back home. And Anthony.
Hello. I'm Anthony Chan from, London United Kingdom.
Excellent. Alright, folks. Let's let's begin with Anthony. And what what did you like as your first choice?
Yep. First is the late breaking abstract, zero zero two from McGonagall and colleagues. This is a study looking at five different classes of biologics in PSA. The PRO SPIRIT study with 1,000 over patients they were gonna look, they looked at twenty four months of the efficacy of the different agents. The TNF, IL1223, IL23, IL17 and JAK inhibitors.
In summary, over the period of time, we found that the IL-seventeen namely execizumab was as effective as TNF and JAK, but there were some differences. The treatment with a execizumab brought on a faster improvement compared to IL-twenty three and also the IL-twelve twenty three in terms of the CDAPS score and also in terms of skin in terms of the body surface area this was better than the TNF. This is quite contrasting to another study which was also presented early in the conference the OP0010 from the TriNetX study where they looked at people very early in psoriasis where before they actually developed psoriatic arthritis in that group it seems that the IL-twelve 23 was better than TNF and IL-seventeen. So I think these two studies perhaps tell us about the continuum between psoriasis to psoriatic arthritis and latent disease that perhaps IL-twelve twenty three or IL-twenty three inhibitors could be operating earlier in the disease in terms of the cytokine signaling and later on the disease it seems like IL-seventeen TNF would be more effective. So I thought that was quite interesting, the LDA-two.
So controversial, isn't it? Eric, what do you think about this data and where is its real utility?
Yeah. So let me follow on with one other abstract and then talk about it. And I think on top of the sarah like a map that Anthony just talked about. The other interesting late breaking abstract was the one on molecule called the zocobep, which is not technically a nanobody, but it is another small protein targeting interleukin 17. In this case, just interleukin 17A and not A and F as the nanobody that they had talked about was.
This was a phase 2b and three study. They'd done some phase two work before. It was a multicenter trial that looked at a couple of different doses of this is ozocobab molecule versus placebo and showed that it was quite effective with ACR 50 response rates at sixteen weeks of about forty percent in both arms, and an MDA response that was also about 40% in both arms. An effective drug with also great skin response at about 50% PASI 100s. So it behaved a lot like an IL-seventeen inhibitor.
And I think the interesting question is whether these sort of smaller protein IL-seventeen inhibitors are going be any different than the antibodies that we've been using for some time, ixekizumab or secukinumab. With respect to the, TriNetX, stuff that Anthony referred to, I actually will want to sort of push back on that one a little bit. I looked at that with some colleagues who know an awful lot more about epidemiology than I do. And the challenge with that particular database is that the data analysis isn't great. It isn't, carefully done.
It's a really interesting, system where you can They sort of layer a dashboard on an existing database that pulls data from multiple EHRs, but it's not really well, structured. And it, I don't know how well you can trust the data that's in there because it doesn't really control very well, for confounders and especially confounding by indication when people select drugs, because you're at the mercy of whatever drug that people are put on. So I would be a little cautious about using that to say that one pathway is better than the other. What we don't have in psoriatic arthritis and we desperately need our, head to head studies comparing some of these newer targets, 17 and IL twenty three. We've had a couple of head to head studies comparing IL seventeen versus TNF inhibitors that both show the same thing that they're equivalent for joints, but IL-17s inhibition is better for skin, but we don't have any studies with the newer agents.
They have them in derm, they've done them in derm, so we know it can be done. They just haven't been done in rheumatology.
So can I Yeah? Here you a few comments in there? So I think the the Ezocobet nanobody, they presented three different new IL-seventy inhibitors at this meeting, and they're all very much ho sixty forty twenty, ACR twenty fifty seventy, and they're all 40% MDA. So that'll make a total of what sticks we're gonna have now. So I would not I'm asking the question, how many r seventy inhibitors do we need?
And if you're not ten, twenty, 30% better, what's the point? I get that we need more than one in case someone has an allergic reaction as you occasionally see skin reaction, sec, kinemab, etcetera, etcetera. But how many? And I was just a little disappointed in these new nanobodies that are supposed to have increased absorption and get into tissue better that they weren't actually getting better responses. And with the TriNetX thing, I hear what you're saying.
They tried to do propensity score. They tried to match for lots of different things. And what was overwhelming was the starve. They had 200,000,000 people and pulled out a million PSOs and a couple of 100,000 PSAs. And everything Eric is saying is a 100% correct.
You you know, garbage in, garbage out. And, really, they just showed that there was a difference in the reduction of the ICD code change from PSO to PSA with one biologic a little bit better than the other biologic. And it happened to turn out to be similar to a previous Thingler paper that said the same thing. But, I think if if there's any way that that can be checked for accuracy, the sheer size of it's pretty overwhelming.
So isn't the on one hand we have the data about what works, what's more effective, what you know you might want to hang and nothing is overwhelming us there. But on the other hand, Trinetix was attempting to answer the question, is psoriasis preclinical psoriatic arthritis? And can the evolution of disease to another twenty, thirty percent who develop PSA be altered by more aggressive biologic therapy? There's been reports in the past that are faulted for challenge bias, right? And there's no strong, strong proof that aggressive treatment of psoriasis will stop the progression to PSA.
So where are we in thinking on this issue? It is
Well, that's it's gotta be it's gotta be prospective studies, Jack. And they're doing it, but with a conversion rate of three percent a year, PSA to PSA, you don't have to follow a lot of people for a long time to answer that question. Don't you think, Eric?
Yeah. I think that's exactly the problem, Peter, is that I the these sort of retrospective looks, there's just too many confounding factors involved to really know for sure. You know, the the challenge with the TriNet database, I I I'm not an epidemiologist, but talking to some friends who did you know, the challenge with the propensity score matching, Peter, is that you can't actually get under the hood with that system. You actually literally click a button that says, please propensity score match, and then it does it. And you really don't know what it's matching for.
And so a lot of numbers
They listed they listed in the presentation. You know?
I understand this. But but the thing is that as you said, garbage and garbage. I mean, more numbers doesn't make it better if the data you're using isn't good in the first place. It just sends you down a rabbit hole. But you're absolutely right.
It has to be done prospectively because, you know, you need to take a large, you know, well characterized cohort of psoriasis patients who clearly have no arthritis or early in disease and follow them out for some period of time and see how many and on what drugs get arthritis. But that's gonna take a really long time. As you do that, you can look for factors, whether they're genetic factors or other biomarkers that may help you predict that, but you need the clinical outcomes to order in order to understand whether any of those matter. And to try to do it retrospectively, people were trying to do this for years and it's too complicated because you have no control over what they received. If I have a patient who has psoriasis and didn't get psoriatic arthritis, is that because they never were going to or because of the medication that was being used to treat their psoriasis?
And I don't know that.
All right, final word on these abstracts. Anthony, you brought it up, you have any final comments?
Yeah, think a very interesting concept of this progression from a PSO to PSA. We do know about risk factors, it'd be worthwhile studying the high risk group people and there was another abstract on high CRP being a predictor of future development of PSA as well. So simple biomarkers but then studying in a head to head comparison would be the best way.
Okay, interesting concept. Eric, what's your, one of your favorites?
I mean, I did think that the small molecule IL-seventeen inhibitors were interesting. The other one that's interesting that I think we don't know where we're going with it yet was an abstract on another TYK2 inhibitor. There's another, so we know that ducravacitinib has been working its way through. It's been approved at least in The US for psoriasis and the sort of claim to fame, if you will, these TYK2 inhibitors is twofold, that the way you can inhibit them is more specific that even though TYK2 is essentially the fourth member of the JAK family, its mechanism is such that you can target it more specifically than you can with any of the other JAK family members is you don't have some spillover. And the problem with JAK inhibitors, as we all know, is sort of off target effects and whether some of these cardiovascular and hematologic issues are related to the efficacy of the drug or other effects that you're not hoping to get.
And the TYK2 inhibitors may kind of get around that. The other issue is the TYK2 inhibitor that IL-twenty three signals through tick two. So the idea is you're targeting a pathway that we know is effective in psoriatic arthritis. You know, it's not as good though. Interesting enough.
Sudacravacitinib is, know, in the data that's out there doesn't look at least for skin as good as the IL-twenty three specific antibodies. So even though it's the same pathway, it probably doesn't block the pathway to the same degree. There's enough that gets past it. This new drug now called Zazocitinib, which I love because I think that's the best generic name for a drug that I've heard in a long time. It's Zaz.
The drug? Takeda drug?
Yeah, Zazo, Sydenham. So they presented some early data and the thought there is that it's higher binding affinity and higher potentially, therefore you can drive the efficacy higher, we're given a higher relative dose and still maintaining specificity. But honestly, it didn't look a lot much different than the ducravacitinib data. So we'll have to wait and see. And we don't have a lot of data in psoriatic arthritis yet.
It's all in skin. But they all carry nice, safety profiles with them. So that's a plus. And don't know that these are going to be drugs for people with the most severe surrogate arthritis or the most severe psoriasis, but for people with sort of modest disease, oral drug that has very few tolerability issues and not a lot of safety concerns is potential win.
Okay, anybody have a comment on the addition of the new tick inhibitor?
I think we we're stuck in our country that we have to use two conventional synthetics over twelve to twenty four weeks before anybody can get access to a biologic that's reimbursed. The methotrexate has to be one, and we're mucking around with leflunomide and sulfasalazine as the others. And we'd much rather use Dukra or even Apremolux, which Right. Was not has yet to be approved for PSA in our country because the government considered it wasn't effective enough at its cost to hold people up getting to better treatment. So I'd love to see Juukka as the second agent we have to try before you go to a biologic unless there's very bad prognostic features.
We have a Preliminary S. Don't worry. You're not missing out on too much, Peter.
It is the best selling of all the newer drugs because of its safety profile and derm seems to like it quite a bit.
Yeah, I love it because you don't have to monitor anything. You don't have to check labs. You don't have to follow anything. You can just, as long as they don't have diarrhea, you send them on their way.
Doctor. Shannon, how do you
really good safety profile for some of these agents and I think early in disease where perhaps the disease is not as severe in the mild to moderate cases a lot of these drugs like Premalas, Thick two I think would be probably where we would start them first before they went on to other drugs because of the ease of convenience of taking it. The binding story, the tighter binding we've had this in the other areas IL-seventeen with ICSI and with the nanobodies yeah you know I think only time will tell whether that's going to make any clinical difference. Early data doesn't suggest that it makes a huge difference in terms of the clinical efficacy.
So is the psoriatic space shaping up to be a battle of the highs and lows, meaning that there's entry drugs that people are going to argue about, which always now has to include methotrexate, but in The United States at least it's going to include opimulast and maybe as the TYK2s get into play and also the JAKs, are they going to be lower end considerations? Then if you have more serious skin and serious joint that you're going to be looking at the biologics, especially the, you know, the seventeens, the dual seventeens, the 20 threes, the twelve twenty threes. Is is there this polarized approach or no?
I think for the for the first time, we get individualized choice depending what domain you've got. And, Alexis showed nicely that, you know, most people have three or four domains involved. And the majority have two, three, four. So if you're axial, you've got an individual choice. If you're skin, you've got an individual choice.
If you're if you're polyarthritis, you can individualize your choice. If you got uveitis, IBD, individualize your choice. So I think the real question is, are we wedded to this methotrexate forever just because of history and just because of safety. If your wife got acute psoriatic arthritis with many joints and some skin, would you start her on methotrexate, or would you go straight for one of the very safe semenines or 20 threes? For example, in Germany, they tell me the derms are allowed to go straight to secukinumab not based on evidence, but based on a court case that they were successful in winning.
The patient, that is. So, you know, my son has a PSA, and he's certainly on one of the newer drugs to control his disease at a young age. So I'm just asking you the question. Are we wedded to methotrexate forever when there are agents that many people think are more effective, less associated with nuisance side effects, maybe more suitable in the long, long term, especially young people who like to drink alcohol in Australia. And what should the first be depending on what your domain involvement is?
Is it not the individualized part is individualized to the prescriber and what I believe, as you're suggesting, Peter? Because the guidelines and rapid guidelines levels the playing field on a lot of these choices because they're really the trial designs proving the point. I get it, I the problem was compounded by the PSA seam study, which showed the efficacy of methotrexate and put it back into play when many of us were trying to move away from methotrexate. Maybe not a safe drug in a psoriatic population, and maybe it's certainly not as good as some of the newer drugs versus what we're seeing, but that study kind of, changed
the I think we gotta get away from it, Jack, though. I mean, why are we using methotrexate? We're using methotrexate because it's been around for forty years. Mean, there's a lot
of stuff
for me that's been around for forty years that we don't use anymore because, things have moved on. And just because it's old doesn't mean it's better. I mean, I would challenge anyone to say that the safety profile of methotrexate is better than the safety profile of any of the biologics we're using, let alone the IL-twenty three inhibitors. And the real reason we're doing that is cost. And that may begin to change.
I think, you know, we're starting you guys in in in The UK and in in Australia way ahead of us on this in terms of biosimilars, but we're starting to see it here. So, you know, when you've got access to a biosimilar version of adalimumab, why do you do methotrexate then? How much money are you really gonna save by putting on methotrexate and monitoring, their their labs and having to do a liver ultrasound on some percentage of them because the LFTs are high? I think we need to get out of that and get away from that.
If you have million people with psoriatic arthritis, do you start them off with a $80,000 a year drug or with an $8 a year drug?
But it's not 80,000, it's a $10,000 a year drug. If you're using a biosimilar and methotrexate is not $8 a year anymore. My patients are paying a couple $100 a month. You know, if you just look at the actual numbers, methotrexate is a 2 or $3,000 drug plus all the lab work you're doing, plus the potential, you know, other workup that happens when you see hepatotoxicity. I don't think it's that much cheaper than the biosimilar atalimumab.
And I think we're going to see even more this whole issue of costs in another year, year and a half or whatever it is when tofacitinib goes generic, because all of a sudden, all of the noise about not using JAK inhibitors may go out the window when it's actually one of the cheaper options.
You know, I think
Doctor Chan can correct this.
Right.
Isn't a biosimilar atom, Alamemiumab cheaper in The UK than methotrexate?
It's cheaper than the subcutaneous not the oral one. So I think this is changing. I mean there's a lot of this is down to you know what the payers are saying. So and we don't actually have a lot of evidence in the use of methotrexate in PSA interestingly. But historically we've always been using it.
But as you say the price is coming down and it is likely that, we will be moving away towards using more biosimilars early on in disease.
Okay. Alright. Peter, give us something a little less controversial.
Well, I was gonna give you I I knew you'd ask, so I thought about the themes, and the themes I found six. New r 17 that you've mentioned, telemonitoring. I think you know about what I feel about never examining patients ever again and missing pathology outside of joints no matter how good the the patients feel about it. This prevention of PSA, the PSA we've already talked about. Biomarkers was a big theme.
But there was a GRAPA symposium, and there's a a presentation on this difficult to treat PSA. And what I liked about it is that they'd hived off complex to manage from difficult to treat. And I think that's an important distinction. And it even comes over to the AXPAS space where one of the new ASAS guidelines is if people aren't responding, reassess the diagnosis rather than cycling forever through expensive biologics. So I think there's parallels.
And the D to T definition, I think they're gonna end up with, is fail one conventional and fail two biologics of a different MOA. And then you've got this label difficult to treat, which has to be reworded as treatment refractory or the patients aren't gonna be happy. And so I'm not a difficult person. What are you saying to me? So, anyway, I think it's a it's an interesting initiative.
Complex to manage means a lot of nonmusculoskeletal pain that has to be managed equally as well, whether it's cannabis, whether it's progabalin, whether it's amitriptyline, whether it's diet and physio and the the GLP one drugs, we can't ignore that, and it's just as important. And the implication is if you're can identify the D to T before they've already failed two biologics, Maybe combination therapy needs to be tested, etcetera, etcetera. So I think the whole movement is only gonna be relevant if it changes management at the people we know are going to end up bad prognosis. So I thought that was an interesting, area that's sort of a hot topic at the moment awaiting definition. And the other one that I was gonna mention was the GO LAPSIS study where, again, asking the question, is a TNF plus methotrexate and some steroid any better than methotrexate and steroid alone?
And I must say, was so disappointed in this study that they wasted this fantastic opportunity by filling all the patients up with injected steroid at baseline. So you only had to have two swollen joints and one enthesus to get in. 40 in each arm, pretty small. Took them years to recruit as it was. Early, early untreated PSA.
And they gave him a hundred and twenty milligrams of injected steroid each arm at the beginning of the trial when they started the methotrexate on one side and the galimumab methotrexate on the other, then they repeated another hundred and twenty eight weeks later. And the the group without the TNF got twice as much steroid as the group that were on the TNF, and then they say there's no difference in between the two down the line. Who's surprised? What a waste of a fantastic opportunity to see if starting the TNF on day one would make a difference. Because that was the that was the conclusion that they couldn't show significant difference.
But when you looked at it, there's a big difference in steroid. The numbers were small, and there was even sort of trends like to separate them even given all that stuff. So, I was a bit disappointed in that study because it didn't answer the questions we wanted to answer. For the higher responses like ACR 70, there was clearly a difference that was significant. But even at week twelve and twenty four with the TNF added, MDA was pretty equal across the board.
So missed opportunity as far as I can see.
Let's go back to the the distinction of difficult to treat and complex to manage disease. Anthony and Eric, what does that do for you in the future management of psoriatic disease? Anthony?
I think it's, the important point here is to revisit the diagnosis. And I think the difficult to treat, patients often we have to take into consideration the comorbidities. So a lot of these patients, we are using scores that might be measuring fibromyalgia or there might be an effect of obesity or smoking. So rather than cycling through biologics one has to kind of take into account some of the not only extras musculoskeletal manifestations but comorbidities as well. And so making the distinction between complex and difficult to treat is quite important.
Eric?
Yeah, I mean, think that's huge because there are two different issues, right? The question is whether you have a disease process, that's not responding to what you're treating them with, whether it's a biologic or a combination of biologics or a different biologic, or is there something else at play that's not going to respond to whatever you change them to. And I, and I'm, as I've sort of to compare, as I've looked out there, I'm a little disappointed in what's happening in the rheumatoid arthritis space, because they're kind of muddying the two together. And, you know, I can't speak for Anthony and Peter, but I I'm not infrequently see a patient who's coming in for another opinion who's failed, you know, three or four or five drugs. And the first question I always ask, and I tell my fellows to ask is, are they actually treating the right thing?
Is this really, you know, is this, if they've not found the drug that's going to work on their disease or is this central pain or something else that no drug is going to work on. And I liked the approach that, the folks at grapple are taking in psoriatic arthritis, because they're really trying to separate those two out And that the complex to manage, includes fibromyalgia kind of central pain includes people with osteoarthritis. It's not, I mean, those are not going to respond to a different biologic, no matter what, or a different pathway of biologics. And if we're going to start looking at approaches to these folks, we need to make sure we have a sort of a coherent, consistent pool of patients who are at least potentially likely to respond to whatever we're going to try. So I do like this approach and I think it does have, legs and they're still trying to sort out, you know, as Peter said, you know, how many drugs do you have to fail and what makes that call.
And that's, that's sort of the, the sort of fine tuning, but the big idea of separating out difficult to treat, you know, inflammatory disease versus complex to manage that takes in all the other pieces that we're dealing with is is huge.
You know
And I left out one key point. Sorry, Jack. I left out that the definition of difficult to treat includes imaging evidence of inflammation, whether it's ultrasound or MRI, but not labs. So that is what Eric's saying. You have to have evidence of active inflammation to be d to t.
Yeah.
So the hard and expensive to treat just got more expensive by throwing in an RN ultrasound. Yeah. I don't know that that's an advantage. I think you can hang your hat on other ways of assessing inflammation, but the one you don't want is empiric trials to see if an anti inflammatory agent is going to benefit those who are not responding. So I'm a little concerned about the clinical trials that we've seen in the past showing poor survival of expensive therapies, biologics and targeted synthetics, in both psoriasis and psoriatic arthritis, such that when you look at three years of therapy, less than half the people are taking the drugs.
I want to know from our experts here, is that because these are the D2T patients or is it because we just have too many options for treatment and people are switching off because they can't? Anybody have a strong opinion on that?
I do. I think in a lot of it's the latter. We've talked about this in our psoriatic arthritis clinic. I work with a dermatologist and we've been talking about this lately as we see people. And the first thing is that the idea that two, three years out, seventy percent of people are off the drug eustardom.
That doesn't feel right. I mean, that's just not been my perception, but it is what it is. They're getting that data. But at least in The U S what I'm seeing is I think a lot of it is expectation that we've got so many drugs and so many good drugs that patients are getting to the point that they're expecting to be all better. And I have people come in and say, you know, this is working well for me, but I've got this one little piece of psoriasis on my elbow, or, you know, this knuckle is hurting me a little bit.
And I try my best to talk them down and say, look, you know, you're not a 100%, but boy, you're 95%. And I don't know how much we're going to gain by starting all over and switching to a new drug and you may be worse. And, but I think people are, especially in the skin side that these drugs have become working so well. People see the promise and they're like, why can't I be clear? Let's get me there and let's switch to something else.
I'm not happy where I am. And I don't know that everybody, that we can expect every patient to be 100% controlled. I just don't know that that's the right target.
Yeah, think the drop off is mainly because it's such an heterogeneous condition and we are treating different domains at different time points early onset, late onset, you know, polyarticular, spinal and what's really important is the assessment of these patients after you before and after treatment to ensure that we've got the right kind of phenotype of these patients and hopefully we will be able to then select you know the right agent at the moment very much clinical but hopefully with the future development of biomarkers we hope we'll be able to choose we become victim of choice that we stop sometimes stop assessing people because we know that hey there's another one we can go to and then we get into this cycle. And this is what we need to be we go back to the clinical examine them check make sure it's firstly psoriatic arthritis not osteoarthritis and then what particular domain is it mTCs, you know, we have to just use that a bit better.
Peter, will we do better if we treat by domain and make it personal as you suggest?
Well, I I do what Eric does. I tell him, like, we have to squeeze every last drop out of each agent before we swap and change, because, firstly, it's been very hard to get it, get access, and then, you know, you gotta make sure that that nonresponse is really something to do with nonresponse to that therapy. But I do think the PSA patients are different to RA, and the numbers prove it that they churn much at a higher rate than, than the RA patients. And I wonder if it's because we often treat late, not early. And I wonder if it's to do with choice.
And I wonder if it's to do with flares from intercurrent infection and a million other stress life stress events that makes it just as difficult to treat PSA and that there's a it's a combination of disease almost getting resistant to what you've used and, churn because you have choice and churn because you have flares and things. So it's difficult. There's no easy answer to why they churn. They always have a high placebo response rate anyway in all the clinical trials compared to RA, and they churn more than the RA patients do for some reason.
I want to ask our panel we kind of went over the sotoluikumab, the dual AF inhibitor vial 17, kind of quickly and this along with bimekizumab on the precipice of maybe being approved in PSA. Is there any belief from the data that we have that these drugs are going to be better arthritis wise? We know they're going to be very good skin walks, right? The head to head trials and psoriasis show that, but are there going to be any better arthritis wise and or any safer in in do anybody have an opinion about this?
Well, I think they're gonna end up the cemidines in many countries like NICE in The UK are gonna make people use a TNF first. And the TNFIR numbers with bimekizumab is pretty impressive. And I got a feeling that in many countries, it'll slot into that position not because of what people want, but because the regulators will insist. So at least to be able to say we've got the best TNFIR numbers in any study, but it's hard pressed to show a difference that blocking f makes compared to just blocking a by itself. And the downside seemed to be a little bit more fungus.
I certainly don't think there's any more IBD, but I'd be interested in the other panelists' just thoughts on that.
I think we select carefully so this is why we probably don't have many people with IBD who will be put on to this treatment. But in terms of the nanobodies, it's too early to say, from what we know. Certainly at twelve weeks it looks impressive in terms of its ACR 50 response. Whether you will fall into DNF IR, it probably will be where we practice currently because of the costs.
Yeah, I don't think it's more effective than the existing IL-seventeen inhibitors. I mean, the problem is we have no comparative data, but if you look at their two phase three trials, they don't really don't from the joint side, they don't really look very much different than execizumab or secukinumab. I mean, Peter's right. You know, the one sort of thing they might hang their head on is that it seemed to perform a bit better than the TNF IRs, but that's a different trial than the TNF IRs that were in the execizumab trial or in secukinumab trials. And I'm a little bit cautious about sort of making too much of that.
And I'm also not sure that inhibiting IL-17F that there's some mechanism why it should work better though. So, I mean, there's no rationale for why it should be better in TNFIR necessarily, you know, that, that the problem, the promise of IL-17F inhibition is really for skin and it works there. It's a very potent drug in skin. But I don't think there's a heck of a lot of difference if any on the joints 17, and that's no different than the other two we already have.
Okay. Do we anybody have any last ones you wanted to get in before we conclude our panel?
Yeah, if I got one it's a more info spa this time if I can share the oral presentation one three two. This was a treat to target approach in SPA which I thought was interesting. It's people very early disease one year disease duration and they put them on galimumab versus anti inflammatories once they got onto remission they came off the treatment but very quickly 84 of them flare but the time to flare was a bit longer in the golimumab group one hundred and fifty five days versus the NSAID group which was sixty one. What it showed is that the male patients low best die and non smokers were the people who are more likely to get into remission. So I thought it was interesting to study this early in disease most of our studies are eight, nine years of disease duration.
And Jack's already mentioned, sorry. Eric's already mentioned the the JAK inhibitors. Well, the Chinese presented AS data and PSA data of a JAK oh, sorry. RA data of a JAK their own JAK one inhibitor, which looks and tastes and smells and feels like a JAK one inhibitor and has results that are unbelievably good. And the safety profile that's also unbelievably good.
The higher dose didn't have any anemia, and the and in fact, they don't show any zoster results. So when you ask them, yes, they had a couple of cases. So we need those molecules out multinational studies, but they'll be quite happy to do them in China and not, see the rest of the world. They've got a big enough patient population. But Eric's right about, TOFA.
They tell me there's eight generic TOFAs in Buenos Aires.
Mhmm. Yeah.
My understanding in India right now is that, generic JAK inhibitor is the drug of choice for RA at this point because it's incredibly cheap. There's a million generic options.
And then I've actually seen a a publication where they compared the generic TOFA against the, originator TOFA and like a biosimilar type study, and that was equally as effective and had the same profile.
Perfect. At the conclusion of meeting, didn't GRAPA Habits meeting at UR, Eric?
They had their meeting beforehand, and I don't recall if there was anything dramatic that came over. They have a number of projects that they're working on, both educational and this whole idea of defining the difficult to treat patient really as a pathway to then doing some clinical trials of that population to really understand the best treatment approach.
So it's a project. Sorry, it's a big project on gender and why there should be differences in baseline disease activity and responsive therapy What's gender? Females.
What blocks? I don't know what you're talking about. Gender?
Pardon?
Gender.
Sorry. Gender. So females have high based on disease activity respond less well. Okay. There's a very giant project underway to work out why that should be and whether we should stratify all clinical trials going forward for gender.
Right. There's a big biomarkers collaboration called Hippocrates. There's a big combination study underway with GRAPA, combo 17 no. Combo twenty three t n f versus 23 alone. But there's there's a number of things underway that are trying to answer some of the issues that you've raised, Jack.
Okay. Alright, folks. This has been a a lively discussion. We appreciate your oversight and review and your careful attendance at all these sessions and and educating us on what's happening in psoriatic arthritis. Have a good evening.
Alright. Thanks
a lot. Thanks. Take care.
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