ACR24 JAK TYK Topic Panel Save

Welcome everyone. This is a nice summary panel from ACR twenty twenty four in Washington, and we are going to tell you a lot of interesting stuff. We're going to talk about the JAKs and the TIC-two. Are they dead in the water? Are they safe?

What's the coolest stuff out there? So I'm Janet Pope. I'm a professor of medicine at Western University in London. David, who are you?

Yes, David Liu from Melbourne, Australia.

Michael, who are you?

Mike Putman from Milwaukee, Wisconsin.

Great, wonderful. So maybe we'll start our first round of discussion and we can certainly feel free to interact. David, do you wanna tell me what you thought was interesting with the JAKs?

Well, I I mean, I'd almost like to hear from Mike first about Select GCA and then leading to a bit about PMR because I'm gonna tell you about PMR after that.

Okay. Let's do the big vessels before the other ones.

Well, let's make sure we don't think the PMR is second fiddle to GCA. That's a

very Oh, it's not too.

Happy to talk about select GCA. So, I was actually a participant in this, although I was not able to enroll any patients. So I want to talk about SELECT GCA. This is abstract seven seventy. This is a nice bracketing because this actually began the meeting for me and now it is also ending my RheumNow coverage.

So it's all coming full circle. But this is a really important study. This is a double blind randomized controlled trial conducted in 24 countries of the Janus kinase inhibitor, upadacitinib, among patients with new onset and relapsing giant cell arteritis. So ever since the GIACTA trial, where we realized that interleukin six inhibition could help us get away with lower steroids and have a better rates of sustained remission among patients with giant cell arthritis. We've been pretty excited about bringing new disease modified anti rheumatic drugs into our armamentarium.

I think a lot of us are methotrexate skeptical. I would include myself in that. And so it's felt like there was a steep drop off for patients who couldn't receive tocilizumab or who didn't respond to it. And so I think there's a lot of excitement about this study in particular. You know, this was a big study and this was a big study that was launched with virtually no preliminary data for the actual molecule itself.

And they went right into it. There were four twenty eight people who were randomized, either placebo, seven point five of upadacitinib, or fifteen of upadacitinib. And honestly, it worked. The plenary session was pretty exciting. If you look at the efficacy estimate, the primary endpoint was sustained remission at week fifty two.

So people got upadacitinib fifteen milligrams and a twenty six week steroid taper. Forty six percent of those people were in remission at week fifty two. Compare that with a fifty two week steroid taper for the placebo group, twenty nine percent remission. So that's a fifteen percent absolute improvement. That's in the context of getting, you know, twenty six weeks shorter steroid taper.

So, you know, the smaller dose, which I kind of would have liked if that had been an option from a safety perspective, really didn't seem that different. And I suspect that we'll wind up needing to use the fifteen milligram dose to get the efficacy that we'd be looking for. So that's one caveat to it. But I mean, if you look at all of the different subgroups within the trial itself, they had a nice presentation of the subgroups as well. It looked like across the board, it worked for pretty much any small slice and dice you could look at, new onset versus relapsing, demographic characteristics, disease characteristics.

And then I think just to go to the most important topic for our Janus kinase inhibitors, which is safety. There were no new emerging treatment associated adverse events. It's tough when you look at a, and this is a big study, four thirty people with GCA is an impressive undertaking, but it's just not quite large enough to say definitively whether or not we see any of the safety risks that we saw with tofacitinib a couple of years back. So still kind of an open question. I'd love to hear from y'all what you think about either of those topics, either the efficacy of the agent or the safety risks that remain.

So

before I commit, if this is approved, which presumably because he went straight to phase three, it would be an add on, an extension of the label. If it's approved, how are you gonna decide upa fifteen milligrams a day versus tocilizumab every week or every other week? How are we gonna decide this?

That's a great question. That's a great question. So I actually am hatching a scheme to compare them in some kind of network meta analysis. It was actually a little complicated. So I don't think we're going to get a direct comparison ever in a randomized fashion, probably not in good comparison observational data for many years.

So I suspect there will be a lot of stickiness with tocilizumab because we have experience with that. And this is where the safety really becomes question. So I approached multiple patients for this trial. It is hard to enroll people into a study when you have to say, Ah, you know, this class of medications has been associated with cancer and cardiovascular disease, which are essentially the two least favorite things of the population in question here. And so I suspect tocilizumab will retain quite a lot of the first line agent status for some time to come.

There's some benefits to an oral molecule. I do think that there's quite a lot of patients who would benefit from this, who maybe didn't benefit entirely from tocilizumab or who preferred an oral agent, various other reasons. But I actually suspect that tocilizumab will retain its kind of first line status for a while now. What do you think, David? I'm curious to hear your thoughts.

Well, it's something that I've kind of ideas I've thrown around with others around the place about this. I feel like we'd love to get to the situation where we could phenotype patients well and there's enough heterogeneity in GCA that we might be able to do that and then be able to select an agent not just on the basis of the general characteristics of a patient and what it might mean for their safety and then the individual characteristics of the therapy, but the actual characteristics of the disease itself. And I guess if you think about maybe if part of the appeal of something like upadacitinib is that by virtue of the pathways it affects potentially it might influence intravascular complications more, if I can assert that. And I guess we've seen data from imaging studies and from histopathological studies that maybe tocilizumab might not have the same effects on large vessels on an ongoing basis that we might like, then plausibly the patients that are less likely to have aneurysmal changes or have other intravascular complications might go to tocilizumab, others might go to upadacitinib. It will start to get interesting though when you start throwing well we've got G Captain which will probably report soon for secukinumab.

So once we start throwing other agents in there it's going to be a little bit crowded compared to where we were. And I say crowded, but Tossy's had it's been eight years now since Geacter got presented at ACR. So it's had an eight year head start on this. And now we're talking about a second agent. So, it's not that crowded, but there's enough opportunity there for us to start to think about strategies.

And it's a really exciting time. We've seen it happen for RA. We've seen it happen for PSA. I mean, perhaps we can reflect on the lessons we learned from those diseases and think about how we might take a strategy approach with GCM.

I love it. I think the bottom line is there will be regional differences, country and county and state differences, and that, you know, the marketplace over time will buy a satisfaction. Can get easier access to this or this one seems to work faster or I have less people flaring when I stop the drug. I think all those things that we won't know till they're in the marketplace to compete with each other, I think that'll end up making our decisions for us. But right now, I think it'll be in a good way a free for all.

Just let's use a steroid sparing drug, go to town. If it doesn't work, a new one and look at relative or absolute contraindications. Yeah, great. It is. It's an exciting time.

So leading from the GCA to the PMR, David, what are you going to tell us about?

I'd like to tell you a little bit about the Bachelor study, which is from our colleagues in Brest in France, Brittany. So that's Alain Saurot and Valerie De Chevelle Pimsek and their whole team, that's Abstract eight fifty eight. And this team have worked over time on looking at treatments for particularly for newly diagnosed PMR. So back some years ago now, they looked at tocilizumab in that context in the tenor study. And then after that more recently they published data from essentially a phase two investigator initiated phase two in abatacept, the Allor study.

So Clare Owen and I wrote this editorial on that study talking a little bit about the difficulties about trying to differentiate newly diagnosed PMR established refractory PMR and the therapeutic approaches to both. And, you know, it's interesting that this came up in the presentation as well because this study looks at newly diagnosed PMR and a newly diagnosed PMR, I guess if we think about our classical PMR therapeutic approach steroids up front, you wean and then maybe you hit some sort of floor up or down, you hit some sort of floor. And in some ways that resistant period is quite different to that beginning period. And so I meant to give you this really long introduction because this is kind of what they've thought about in this study. With baricitinib we've got a four milligram tablet, a two milligram tablet in some jurisdictions, and what they did here is that they had twelve weeks of four milligrams, twelve weeks of two milligrammes and then nothing for another twelve weeks and compared that to placebo.

And obviously, perhaps completely unsurprisingly, baricitinib absolutely smoked placebo. So at twelve weeks twelve weeks of four milligrammes it was in terms of the primary response, was seventy seven percent versus thirteen percent. After you dropped down to milligrams for another twelve weeks, eighty eight percent versus fourteen percent. But I think the really impressive bit is that once you stop, so that's only 24 overall of baricitinib, we're looking at seventy six percent versus fourteen percent and that's an effect size you can write home about. So you know really what we're talking about here is that if you've got safety concerns about baricitinib and you won't know from a short you know phase two trial like investigator initiated phase two trial like this but we're only talking about twenty four weeks of exposure of which half was at a half dose And I think people have concerns about cardiovascular and cancer risk with JAK inhibitors in PMR potentially, or maybe even cost of JAK inhibitors in PMR, but a short abbreviated approach might deal with both of those things.

It was really a brilliant study design because it was four, then two, then off and still showed as you see a huge effect in steroid sparing. Contrasting with the methotrexate did not show any steroid sparing in PMR. So PMR news, de novo methotrexate plus PRED versus PRED alone was, in my opinion, nail in the coffin for methotrexate, at least with de novo. I'm not saying problem patients later, and PMR did nothing. So the big contrast of the berry study that was done.

Mike, any thoughts on this? You're gonna

change No, your I have pinged off of both of those. I mean, I have long been methotrexate skeptic in both GCA and PMR. There was a sort of encouraging trial published in analysis of internal medicine quite a while back, I think like 'nine, for methotrexate, I don't if I can help some, but especially in GCA today has been pretty underwhelming. And so I often skip straight ahead to anything else in PMR. The baricitinib study was quite interesting to me.

I enjoyed the presentation of it as well. David, my question for you. So we have all these agents coming down the pipeline and I think our historical PMR taper was somewhere between nine to fifteen months, depending on who's running the show. How is this modulating your approach to steroid tapers in PMR? It's a tight issue.

It's a tough thing to decide.

This is a great question. And I've heard you talk about this before. I've had conversations in the last twenty four hours about this. I think in the context of these data, I think what's clear is that a single stereotaper for everyone is unlikely to be appropriate. Some people clearly can go faster, some people clearly need to go slower.

And right now we're poor at differentiating who does what. It does make us, if you go back and you think about how we came to the point that we have and I think if you look back at say not that long, maybe twenty years ago about Marco Cimino's work on trying to figure out optimal steroid dose at different points in time, I think now we've got more data and the capacity to generate more data to actually not just only think about a quicker steroid taper as the base case but then also really trying to get the characteristics and build a strategy on this. What we really need of course I think is a study, that has multiple arms that compares faster steroid taper in the context potentially of JAK inhibitors or other things that you might use in newly diagnosed PMR and build a strategy from there. Now, of course, that's wishful thing. Hope some philanthropist comes up with some money to put this down on the table to fund this study.

But I think that there's enormous potential for a common condition to be able to change a lot of lives if we get a better strategy. Because I'd argue right now that newly diagnosed PMR is probably the biggest cause of steroid addiction in medicine and we need to try and do better on that.

Yeah, I love the And word steroid just, I guess a question on all this that we can't answer today is there was a, I think it was a study from China, multiple sites in China, RCT of tofacitinib five VID, no steroids in PMR versus steroids. It was actually statistically and clinically relevantly better. So, you know, JAKs might have a role where it's a very rapid steroid taper. And I mean, the biggest biomarker for me is, I guess, if they're achy again and it sounds like it's the PMR as opposed to mechanical back pain and shoulder tendinitis achiness, we just go up a little bit and go down a bit more slowly. But I mean, these are really they're going to what we're talking about is going to change practice.

So I'm going to shift gears for a second. I want to talk about something we don't talk about that much on RheumNow. So inflammatory myositis, and it's really I'm being Jack focused. So there might be other cool stuff, I'm concentrating on the Jack's. So the first abstract three forty eight was on upadacitinib fifteen milligrams a day and showing that it could be effective in inflammatory myositis, including our traditional synthetase, but also the MDA-five.

It was a small ish study, but did show some pretty good benefit, uncontrolled selection bias. Some of them had failed a lot of drugs. So then looking at a bigger study number, I think it was seventeen thirty six. It was an oral presentation. So it was looking at tofacitinib in inflammatory myositis failing some stuff, comparing it to using the CNI, so tacrolimus or whatever other CNIs.

And it was a large study, but it wasn't like just to know there could be channeling bias. It wasn't randomized, but it was two ninety patients inflammatory myositis on TOFA and two twenty five on the CNI. So quite impressive numbers and they showed survival and benefit overall better in the TOFA group than in the CNI. So very interesting. I kind of wish if they had known their ends would be that large that they would have done the protocol forward thinking and randomized or cluster randomized.

But I mean, that was very telling to me that when I'm in trouble with my myositis patients, especially these MDA-five, because they can die rapidly of their lung disease, if we can improve survival on one product class compared to another, it might really change my practice. Of course, not approved for this, so you know it's an off label thing and no RCT in that. So then it takes me to a wee little RCT number 17 31 Baricitinib four milligrams a day and the problem there's a problem with this trial design but first of all it was 15 patients investigator initiated they got a grant from Lilly to do it probably took a long time to enroll so these people had to be recalcitrant so inflammatory myositis more dermatome than poly but basically either could have gotten in they'd have failed a couple treatments to get in. At least one or two advanced therapies and of course failing steroids where you can't get it down. So okay, all that makes sense.

Nf-fifteen doesn't make any sense to me, but whatever. Let's see what they did. So they did if you remember the REMS study, was rituximab and myositis where it was rituximab versus rituximab at the end of the year. We don't know who wins because they all got rituximab. It was the same design sadly.

So what they did was so they denied you adding Barrie for the first twelve weeks in one group or you got it from day one when you signed the consent. Then at twelve weeks, everybody's still on baricitinib for another twelve weeks and the outcome is at twenty four weeks. So if does Berry holding it for twelve weeks make any difference by giving it at twelve weeks to twenty four or giving it at zero to 20 four? And the answer is nope, doesn't make any difference. But what they did do that wasn't in their abstract but was in their oral presentation, they actually presented that at twelve weeks of berry, so the second group who got no berry was I think clinically relevant and statistically better.

The lead time of getting berry early was starting to attenuate by twenty four weeks. So I think their outcome measurement was at the wrong time and the way the guy presented it, it was the twelve week data certainly in my mind showed that berry in these difficult to treat patients of four milligrams a day seemed to make a big difference. So my take home is I'm going to think about Jack's more 100% off label when I have problem patients. I'd already thought of it with calcinosis and my results on calcinosis and these really problematic, long standing dermatome patients is that it probably takes a heck of a long time. First, you sort of stop getting new ones and then maybe over many months or even in my opinion, a couple of years, you start breaking down the calcinosis more.

So let's open it up. Any experience or any thoughts about either the studies or your own practice? Is this a game changer or not?

My own practice, I've actually been Jack Cureus and myos for a while now. There was actually quite a strange study published in 2019 in a New England Journal that looked at tofacitinib alone patient with MDA-five, and it compared patients who got it to a historical cohort. So as you've alluded to, the science in this area hasn't been quite as solid as I would like, but it at least got me curious about it. An interesting group where I have tried it with some success is actually patients with antisynthetase syndrome, and especially have refractory sort of joint pain symptoms, where I feel like that's one of the main phenotypes where I wind up seeing that. And I've had some people who responded quite well to it.

There is actually a phase three RCT of brepasitinib that's starting now. It's a TYK2 JAK1 inhibitor for patients with dermatomyositis. And so, you know, I'm always excited when I see that there will be a more definitive study coming down the pipeline. And I think that was pretty interesting. One of the things I looked up while I was at the meeting to find out if there was something we could participate in.

Yeah, no, I love your take on all this. I think also Jack's work on skin for dermato takes a bit of time, but it seems so because again, we're only doing the recalcitrant treatment kind of patients. David, any other take on that?

Yeah, I mean, I think it's the other thing which is probably a very small patient population that has been discussed a lot are the MDA-five patients who, you know, tofacitinib seems to be potentially the most promising therapy in a really high mortality, difficult to treat population. We've had some kind of local success with that in N equals two, but I think that we're starting to see more data generated on that. I think at the same time, I think there's been a bit of work on Uber in my side as well, on general IIM. So I think in between those two extremes, we're going to be able to find a few different on label, off label pathways to getting DEK inhibitors for myositis patients. And it is one of the conditions where still, despite more data for IVIG and despite kind of other attempts at steroid sparing, we still use a load of steroids in myositis patients no matter how you splice or dice it.

So I think there's a need there. There's clearly a need there. Then the one thing, generic TOFA could potentially change it all, and that probably applies separately.

With less cost for most countries once it's generic for an oral small molecule. Let's switch gears. Is the safety put to sleep now of JAKs and TIC twos, whichever whichever one wants to give the opinion first? Are we worried? Not worried?

Oral surveillance almost didn't come up. There were only a couple abstracts on that I was kind of relieved. Woah.

Dave I'd like you to start. I think we think it's been put to sleep but in opposite directions so why don't you give your face first?

So I think so I mean there's still ambiguity right and I think that we will have more data that will come in due course and I think the next one to see will be the baricitinib post marketing requirement. And so what we'll have when we have those data is first of all we'll have two randomised control trials to look at safety and that will be helpful in trying to validate a signal. We'll have it across two different agents. So I think the risk that this is a chance or that this isn't a class effect will start to wash out a bit more then. So as much as we've got a break from talking about oral surveillance now then soon enough we'll be talking about it again if we've stopped talking about it.

I think we still are as much as we haven't talked about it, there were enough there's enough posters about JAK inhibitor safety to make me think that we still haven't fully thought about the implications of how to process JAK inhibitor safety in our everyday practice. I think we still bias one way or the other. We still use heuristics that kind of push us probably away from where we need to be. So without trying to sit on the fence too much, I think we probably are starting to we've gone through the hype curve, we went all the non jacks and everything was great, then safety data hit and we went the other way. I think we're getting to the nice middle bit where we're using it with the equipoise it needs.

So having said that, you throw some more data that will come out there and I'll probably swing the other way and we'll be off balance.

You're you're you're making a decision, but it is a hedge, and that's quite okay. Mike, you're on the like, tell us where you're sitting.

Oh, that's been I I think that's very well put by David. I like the historical perspective on it. So I'll give a different temper, my current approach to how to implement these. I remain convinced by oral surveillance. I think that topocitinib among patients with cardiovascular risk factors, there's a risk for cardiovascular disease.

And I think that there's a real risk of malignancy, certainly in folks who are older. So when I, if I start tofacitinib, I always say that there is a definitive, it's a small risk, but it is a real risk. And I think that people need to be informed of that. My baseline assumption is that this is a class effect. I think that the JAK inhibitors are certainly different and there are different selectivity among the JAKs, but there's bleed over.

And I think it's implausible that there'd be a large difference. Now, flip side is it doesn't have to be a large difference. If there's a small difference based on the selectivity, it's possible that one that was more selective in one direction or another could be less risky. So I think that some of the observational data, I think David covered a really nice job covering a meta analysis that looked at this topic, has made me feel like perhaps I should give more credence to that than I have been. And so if I'm starting a more selective JAK inhibitor, I will say something like, I do think that this is likely to be a class effect, but it may not be.

And so I think that can be helpful. And then I actually don't expect this to necessarily extend into some of the less JAK ones like the tick inhibitors. I don't think we've seen that signal. And I think those are sufficiently different that I wouldn't be as comfortable labeling that as a class effect there. Ultimately, is kind of a, I think the companies ought to run the trial if they want to exonerate the drug.

And so I've been advocating for that. I don't think it's going to happen for all of them, but I'm looking forward to some of the data that's coming down the pipeline.

You're raising good points. My take is what if really all our treatments reduce cardiovascular events, but some reduce it more? So that's my take for cancer. It's harder for me to say that our drugs reduce cancer and that one reduces it more. I really don't have that paradigm, but I'm pretty certain in my own made up view of the world that JAKs don't increase cardiovascular risk.

It's just for some reason TNS or certain TNS probably reduce it more. But you know it's a take on the data. It's still seeing a differential that's there and you can't explain it away. So I think before we say it's a wrap, to let the audience know that do Cravasidenib in psoriasis, FDA said you have to do a trial to look at cardiovascular infection and malignancy. So we're going to have oral surveillance by a different name of ducravasidenib, different disease, psoriasis.

And I'm not sure what the comparator is. I think we will get something more definitive there, but it's unrealistic to run studies for four to ten years as the patent clocks tick on all these drugs. You either are in with generalization or you run your study and you say, I'm lucky to be different or I am different or not different. So I think that's kind of a wrap on what we're thinking about. I think the final thing is as a positive is with all these new potential indications, GCA for a Jack, PMR for a Jack, maybe inflammatory myositis when the actual RCT is done.

I think that that will help reassure us that there's still unmet need and a whole bunch of prednisone always has more cardiovascular risk than almost any other drug of a rheumatology drug that I would give the patient. So I think we can always say if we can do better to control the disease and lower the glucocorticoids, we're going to have a better life for our patients. And of course, we'll have two big trials in lupus that will get some data to both upa at the higher dose thirty milligrams. That's a dose that is used in induction and stuff in IBD and also do crevosidenib at the regular dose. So more will come.

Any last words before we sign off, Gang?

Well, I'm glad to see that we're going to eventually get more data on Dukra and safety because I think it's potentially an enormously useful drug. We saw some data at this meeting about persistent effect of dukra in different indications. I heard Mike talk about it very articulately. I think it's, you know, just because TYK2 is a JAK doesn't necessarily mean that a TYK2 inhibitor has the same issues as a JAK inhibitor. Like I've saying to you guys before, you know, a race car and an ice cream van are both petrol powered vehicles doesn't mean that they have the same safety risk.

And so I think if ZUCA has good safety like potentially it seems from the clinical trial program, then it could be an enormously useful drug as add on therapy across a number of different indications. Think cost aside, I'm quite excited about it as a therapy, more so than I thought I would be.

Don't think I can beat either of those for final thoughts. Prednisone's the worst an ice cream

That's cup our final bottom line. Prednisone's been bad. It's

good enough.

I'll give my final 2¢, which is that, you know, when I was told to them I was doing this panel tonight, they said, Isn't the conclusion that JAKs just kind of work for everything? And my first answer was like, Yeah, I guess every single time we've tested them, they seem to work. The SLE brave, but mostly across our diseases, they seem to have some efficacy. I think the real task of becoming five to ten years will be defining where they're the first line and where they're clear second or third line. You know, I'm excited about data in psoriasis, but we were talking earlier about, is that really gonna go head to head against the 23s?

And, you know, in rheumatoid arthritis, I mean, the JAKs are fantastic. Where do they land for myositis? Questions like that are the things I'm really gonna be looking forward to finding out.

So people are gonna have to keep following us at RheumNow as we cover meetings and we'll get the answers. So thanks, it's a wrap.