EULAR 2024 JAK/TYK Daily Topic Podcasts Save

This is the UR 2024 podcast. You're going to listen to daily reports on JAK and TYK2 inhibitors. This was sponsored by BMS. Enjoy.

Hi. This is, Eric Ruderman, from Northwestern University in Chicago coming to you live from the, EULAR twenty twenty four meeting in Vienna, Austria for RheumNow. I spent some time at this meeting looking at a number of abstracts and other information that we're seeing relative to spondyloarthritis. And several questions have come up to me this week. One in particular, I have struggled with is whether we truly need more interleukin seventeen inhibitors and more JAK inhibitors for spondyloarthritis, either psoriatic arthritis or axial spondyloarthritis.

The number of trials that we're seeing, the interest from industry would suggest that after the success of the existing IL-seventeen inhibitors, there's a lot of interest in identifying new drugs going after this target. I'm not sure that the market is going to bear all these different drugs, but the number of papers and abstracts and the amount of information where they're seeing at this meeting is pretty impressive. These include newer antibodies directed against IL-seventeen, and in particular one that we've seen before, bimekizumab, which is a monoclonal antibody that targets both IL-17A and IL-17F, two versions of IL-seventeen, which is distinct from the existing approved monoclonal antibodies that target only IL-17A. We've seen data, and at this meeting, there's

data

on IL-seventeen nanobodies. These are smaller parenterally injected molecules, that don't have some of the limitations of full on antibodies. In theory, they're being used in cancer, and in theory, they may have better tissue penetration. Not clear that that's really the case in our diseases, and, whether this translates into improved clinical benefit has yet to be seen. There are a few small molecule inhibitors, that can be given orally for IL-seventeen and IL-twenty three that are early in development, nothing here at this meeting particularly.

But we're also seeing some additional data on oral JAK inhibitors at this meeting, including a new JAK1 inhibitor that's being studied at axSpA. And we're seeing data on TYK2 inhibitors, TYK2 being the fourth member of the JAK family. The rationale for TYK2 inhibition is that interleukin 23, in particular, signals through TIC two, and interleukin 23 being an important cytokine in spondyloarthritis, it suggests that this might be a better pathway for JAK inhibition, or at least JAK family inhibition, for these diseases, potentially, and I say potentially, with a reduced, risk of adverse events. Some of the things we've seen at this meeting, abstract, OP-one 195, which is a phase two study of Sonalocumab, a new interleukin 17 nanobody that targets both IL-17A and IL-17F. And there's also an abstract for Ezocopep, a nanobody that targets IL-17A that's being presented as a late breaking abstract number five.

Also at this meeting, there's some data on vunekizumab, another IL seventeen a inhibitor, that's poster o eight zero three. And one that I thought was interesting is an abstract on taq two seventy nine. That's a, selective TIC two inhibitor. This is a phase two study, being presented as an oral presentation, abstract, o p o one three eight. One of my favorite, things about this particular molecule, it has had it has acquired a generic name, which is zosacitinib, which I think is one of the best generic names, for a small molecule that we've seen in a while.

All of these, are showing great data in psoriatic arthritis or axial spondyloarthritis, and so there's no reason to suspect that they're not effective molecules. I think time will tell whether the TYK2 inhibitors are not only effective but potentially safer than the existing JAK inhibitors. But I just don't know if we're going to need this many agents targeting the same pathway for these diseases. We'll see. And I think ultimately once these trials are run through into phase three, and hit the market, the market's gonna tell us what is necessary.

So that's my thoughts on this coming to you from, EULAR twenty twenty four, for RheumNow. Stay tuned for more information from this meeting.

Hi. I'm doctor Janet Pope. I x or tweet at Janet Berdo, and I'm reporting today, for hashtag ULAr twenty twenty four with the AtRoomNow group, and, hopefully, you'll be following us for up to date reporting. I want to tell you why ULAAR twenty twenty four was worth the euros. So there's three reasons why, and it's all about in this update on giant cell arteritis and polymyalgia rheumatica.

So giant cell arteritis, the late breaking abstract one, which hasn't been presented yet, is on the positive RCT of upadacitinib and giant cell arteritis being steroid sparing. So two IL-6s are going to work in GCA and now we have a JAK inhibitor. There's other things happening in GCA. There's insights into residual inflammation after treatment of GCA with tocilizumab or an IO6 inhibitor. So on repeat biopsies in OP0233, one third of the biopsies that were repeated at six months on a protocol still had active GCA despite in general having suppressed inflammatory markers.

Now, most people don't consent to repeat biopsies, so I don't know if there was something different about these patients. The next thing is what about when you stop drugs? What happens? This is stopping tocilizumab and polymyalgia rheumatica after six months because then you could have a rapid taper of glucocorticoids. Well, the good news is after six months following for up to a year, one quarter didn't relapse.

The bad news is three quarters did relapse, And that's oral presentation six twenty one. One last thing, a thought on PMR, and I chose this abstract because it's clinically relevant to me. This abstract said looking at the data from a study of patients that were collected, they said leflunomide twenty milligrams a day was better than methotrexate, albeit at a lower dose of about ten to fifteen milligrams once a week. Leflunomide was more effective for both prednisone sparing and preventing relapses. I haven't thought about using leflunomide too much.

I think methotrexate was under dosed, but leflunomide might be an option for our patients, especially if you can't get access or it's not indicated for some of the biologicals that are being looked at in PMR. That was poster zero two eight o. So I think you have three reasons why in GCA and PMR why EULAR twenty twenty four was worth the euros. Please continue to follow us. Thank you.

Hi. I'm at Janet Bourdeaux is my ex name, Janet Pope. I'm reporting for At RheumNow at EULAR twenty twenty four in Vienna. I wanna tell you about JAK inhibitors for new indications. There's three newer indications that you might or might not be aware of.

Baricitinib has been approved in some jurisdictions for alopecia areata, four milligrams a day, no cardiovascular or VTE signals, And the SALT score, which is the proportion of alopecia left behind, was quite a high level where patients did very well and obviously better than placebo. So there's hope for our patients with autoimmune alopecia. The next thing is upadacitinib has been approved for Crohn's disease. And Crohn's disease has an outcome called C. Dye.

So not our clinical disease activity score, but it's a Crohn's score. And the word on the street is that looking at the positive RCTs of upadacitinib at thirty or forty five milligrams a day for induction is that the scores were rapidly improved and far higher than some of the other comparisons that the Crohn's docs are used to. So keep an eye in that space. Then also hot off the press in June 2024, AbbVie announced that upadacitinib is now indicated for kids greater than or equal to two years with active polyarticular juvenile idiopathic arthritis, as well as psoriatic arthritis in children. And so that's pretty interesting.

Tofacitinib, about a year ago in 2023, was also approved in polyarticular JIA. The newest thing is not an approval, but a positive study. So in April 2024, the phase three trial of GCA for upadacitinib usage, which was called SELECT trial, showed positive results in patients with giant cell arteritis. What else is happening in JAKs? The JAK inhibitor upadacitinib and the TYK2 dekrevosidenib are moving into lupus trials.

They're already in phase three. The trials are recruiting or maybe are even nearly recruited. So we'll have data in a year or so. Lots of new indications for JAK inhibitors. Keep your eye on this space.

Janet Pope reporting. I hope you'll continue to follow us at RheumNow. Thank you.

Hi, everyone. This is Aurelie Naj reporting live from Vienna at Tulare 2024 for RheumNow. There is a super trendy topic at the minute, which is pain. It is unfortunately has been an issue for a lot of people living with arthritis, experiencing pain, and sometimes it's very difficult to treat specifically as there are many different mechanisms for pain and some can be related to inflammation and some aren't and and we don't have really good drugs for that. And so there have been discussions as per whether some biologics or targeted synthetic DMARDs could be better than others in addressing pain and pain in its different mechanisms, whether it's nociceptive, nociceptive and so on.

And so there's a couple of abstracts in that aspect that looked into that more specifically. The first one is OP 72 and that study was the select compare study. So it was a randomized controlled trial looking at upadacitinib versus placebo versus adalimumab. And so what they did in this study I think was really smart is that they separated specifically different type of the effect of the drug on pain and they call one of them the indirect effect that is measured by surrogates of inflammation, which would be swollen joint kind, ESR, CRP, but also what they call the direct effect, which is more related to either pain specifically in the patient global or the number of tender joints. And by doing that, they looked at twenty six weeks and they compared upadacitinib, placebo and adalimumab.

And what I found really interesting there is that first of all, we see that both super decitabine and adalimumab do reduce pain as early as two weeks, which is great. That's mainly through indirect effects and inflammation control. And in terms of control of inflammation, both treatments atolimumab and upadacitinib were similar in how they improved pain. However, when they looked at the direct effect on pain looking specifically into the tender joint can't, they were able to show that upadacitinib showed an improvement of that aspect twice more, two times greater at weeks twelve and twenty six that than adalimumab. And so that is suggesting that there might be something in a jackstep pathway that is related specifically to pain and it could be through the nervous system.

It could be there are people studying that at the moment and looking into what are the specific mechanisms for that. But that's definitely something to follow-up on. And that is leading us to the second abstract, is OP 86, which was a study called be real, RAB real study. And that study looked at it was an observational study based on perspective for three years looking at people with RA treated with baricitinib or any other biologic and targeted synthetic DMARDs. And so what they looked specifically at there was the association of pain in the context of remission or low disease activity at three months after starting a new treatment.

And they compared the baricitinib cohort, the TNF inhibitor cohort. And so they were looking at those people that improved their pain by 30%, fifty percent, seventy percent basically. And so what they show is that those people that were treated with baricitinib, while there was no difference in the achievement of a 30% pain improvement amongst group, there was a difference percentage of people achieving an improvement of 50 or seventy percent was sixty seven 46% in the Bari group, while it was fifty seven 41% in the other mechanism of action group. And so what it's showing, it's a different way to look into, you know, achieving pain improvement, although it's not looking specifically at the different types of pain. It's also telling us that there is some form of difference in how JAK in this context, Barry improves pain.

But I think it's a general JAK inhibitor effect rather than a specific compound. And that's kind of encouraging and you know, it makes me wonder and I don't know if something that you do already in your practice, surely don't, although we do think about it as so we obviously in the absence of contraindications or prioritize JAK inhibitors in these people that have very, very strong pain compound component in their rheumatoid arthritis. So that's definitely something to keep in mind and maybe to look further into. It's now time for me to go back to the conference and I will make sure I report anything else I found exciting for you guys later. Follow me on Twitter orilleryroom or follow RheumNow, and I'll see you around.

Hi, it's Doctor. Janet Pope reporting at RheumNow from EULAR twenty twenty four in lovely Vienna. I'd like to give you the top three messages about JAK inhibitor safety. So I was part of a debate, and the debate was today on topic of are regulatory bodies too harsh in the recommendations on JAK inhibitors with respect to safety and restricting prescribing. And the bottom line that came out of this debate, as well as the data that both David Liu and I reviewed are avoid JAK inhibitors in high risk patients.

And there's risk and then there's high risk. So the risk is all kind of relative, so to speak. So the higher risk patients from oral surveillance that was looking at safety was age over 65 ever or heavy or current smoking, high cardiovascular risks such as already having myocardial events, and high malignancy risks such as smoking, older age and more in men. So the audience voted slightly more than half that the regulations are too harsh. So what would I say?

Top three things. Do a shared decision with the use of JAK inhibitors and use them in caution when appropriate and high risk patients or even medium high risk patients with cardiovascular malignancy risk. Do stratify the risk as some risks are far more relevant. Past MI or revascularization is a lot higher chance of having another MI than borderline high cholesterol or mild hypertension. And smoking is a big risk.

So my call to action is identify who's smoking and try to help the patient stop smoking. That should reduce their cardiovascular risk, and it also decreases over time the risk of cancer. Please follow us with lots of reports at RheumNow. Thank you.

Hello. I'm Jonathan Kaye reporting from EULAR twenty twenty four in Vienna. Yesterday, Kevin Winthrop from Oregon Health Sciences University presented two very interesting papers, both about immunization with herpes zoster vaccine in patients treated with various biologics or targeted synthetic DMARDs. He presented one paper about patients who were on upadacitinib in the SELECT COMPARE study who were immunized with a dose of recombinant herpes zoster vaccine at baseline and another at eight weeks after that first dose. The patients who continued to take both upadacitinib and methotrexate developed both humoral immunity and cell mediated immunity to herpes zoster virus.

In contrast, patients in another study that he has been conducting who were taking abetacept either intravenously or subcutaneously were immunized with a similar schedule to receive either the recombinant herpes zoster vaccine or placebo at baseline and then eight weeks later. And in contrast to the patients continuing upadacitinib, there was humoral immunity in about two thirds of the patients receiving abatacept, but no cell mediated immunity. This study is ongoing but suggests that abatacept should be stopped perhaps two weeks or even four weeks before vaccination. However, the exact timeframe with which to stop abatacept before herpes simple the herpes zoster vaccination has not been established. On the other hand, patients receiving upadacitinib and probably other targeted synthetic DMARDs, JAK inhibitors, can continue taking the JAK inhibitor and methotrexate without stopping and still develop immunity to herpes zoster vaccination.

These studies are important because patients on JAK inhibitors are at increased risk of developing herpes zoster, And it's very important to immunize these patients ideally before beginning a JAK inhibitor. But certainly, if they're started on the JAK inhibitor, herpes zoster vaccination should be performed as soon as possible. For more about this and other studies from EULAR twenty twenty four in Vienna, go to roomnow.com. I'm Jonathan Kaye, and I look forward to seeing you again soon.

Hello, everyone. My name is Youssef. I'm a consultant rheumatologist from Leeds, United Kingdom. I'm reporting for RheumNow Live, from Vienna to cover the EULA twenty twenty four Congress. Today, I would like, to talk about, JAK inhibitor.

As, we all are aware, JAK inhibition treatment has revolutionized therapy for various, autoimmune rheumatic diseases, including rheumatoid arthritis. However, this strategy has become under scrutiny, over the last couple of couple of years, since the publication of the oral surveillance, clinical trial data. In this oral surveillance data, they found that, there was increased risk of malignancy and also major cardiovascular events in patients treated with tofacitinib compared to TNF inhibitors. Therefore, the, regulatory, have issued a warning to be careful in using a JAK inhibitor, particularly in those, above 50 years old of age and also with multiple comorbidities. One other aspect as well is pertaining to infection.

The data from the randomised controlled trials as well as the long term extension studies did show some increased risk of opportunistic infection as well as herpes zoster. So does this data reflect in the observational study? So, Jackpot is, one of the largest, collaboration of registries which involve 14 registries in the Europe, and also Canada. So in this study, the main aim is, the main aim was to compare the infection risk, and also Herpes Zoster risk, between patients treated on JAK inhibitors, versus TNF inhibitors and also versus other mode of action. So other mode of actions include including rituximab, tocilizumab, abatacep, and etcetera.

And this presentation, the abstract number was OP0092. So in this study, a large number of patients were involved, were over 50,000 treatment, starters that were analysed. And looking at the key results, there was no, increased risk of, any infection or, severe infection between patients treated with JAK inhibitor versus TNF. The anti serious infection rate was quoted as nine out of one hundred patient years, whereas TNF is seven out of one hundred patient years. To me, this sounds still a little bit low for a real world, and this is sometimes what you might expect with observational registry data because there potentially could be some reporting bias as well that's not been captured.

In terms of other comparison, those treated with other mode of action had a higher rate of any infection and serious infection compared to the TNF inhibitors. Also, it's important to let you know there were some baseline, characteristic differences, not a lot, but, there were two that I could detect. One were, due to the disease duration. So the TNF inhibitors group, had much less, had less disease duration compared to the TNF and other mode of action. And consequently, in terms of biologic naive, so they were more proportion in the TNF group compared to the JAK.

So this could potentially also, influence the infection outcome. And another important key here was regarding to the Hirschspritz zoster rate. And in this real world data, it showed that the incidence ratio were two times more likely in the JAK inhibitor groups compared to the TNF, whereas there was no difference between the other mode of action versus TNF. So what this data showed that in the real world there was no difference in terms of risk of infection. However, there was increased risk in terms of herpes zoster and how this may impact our clinical practice.

So I think we need to think of some measures, to reduce infection risk, not just in JAK inhibitors, treatment, but also in other biological treatment. We can counsel patients to help with other modifiable risk factors such as to stop smoking and to live an active life and some exercises, but also try to help manage their comorbidities better such as diabetes and hypertension, for example. And importantly, with regards to the zoster risk for the JAK inhibition group, We also like, we also want to, advocate, vaccination, shingles vaccination in order to minimize the risk of activation. And certainly this depends on has been done in, other health care services. For example, in The UK, we can only administer, a single vaccination in a patient with, autoimmune diseases who are 50 years old or older.

So I hope, you found this summary useful, for your clinical practice, and follow me, and RheumNow for more coverage of the Congress content. Bye bye.

David Lu here from EULA twenty twenty four in sunny ish Vienna, and here to talk a little bit about one of the most anticipated abstracts, the Select GCA study, which was presented as a late breaking abstract today, PBALBA0001. So the late breaking abstract was for the study that looked at upadacitinib versus placebo in giant cell arteritis. And we'd already heard that there was a positive result in a press release about two months ago. And so everyone was really interested to see what the actual results looked like. So this study looked at two different doses of upadacitinib.

Seven point five milligrams, that's half of our normal rheumatoid arthritis dose, and fifteen milligrams daily. And in fact, the seven point five milligrams daily just missed out on hitting the primary endpoint. So the p value was 0.057. So just missed out on that. But the fifteen milligram woman truly hit the primary endpoint, which was the proportion of patients achieving sustained remission from week twelve through to week fifty two.

And we saw that at forty six percent in upadacitinib fifteen percent group versus twenty nine percent in the placebo group. So, I think that's quite a nice result. I mean, it's certainly of the magnitude that maybe we would have expected from tocilizumab as well. They did a whole lot of secondary endpoints, and you can see actually that the steroid spared is is about over the course of the fifty two weeks. They gave upadacitinib a twenty six week taper versus a fifty two week taper and placebo, And that saved about one point two grams of of of prednisolone.

And I think critically, what everyone was looking for was about the safety. Because all the And inevitably, was a question about, well, given the regulatory safety warnings, should we be And thinking about the kind of disease that GCA is with relatively high median age, is this the kind of thing where we should be using it, a JAK inhibitor? So firstly, say, within this twelve month period of time, of all the types of things that you might be concerned about, actually, upadacitinib came out really well. So major adverse cardiovascular events, there were two in the study, both of which in the placebo arm. Serious infections were actually lower in the upper groups versus placebo groups probably because of the steroid.

And I think it's a good opportunity to remind ourselves steroid is what drives a lot of this in terms of a problem. And actually, there wasn't really much of a zoster signal either. And non- and malignancy, didn't really see much, although it's too short of a period of time as well. Nevertheless, I think it makes a really interesting point and one actually that came up in my debate with Janet yesterday, which is really about trying to- in terms of when we try to assess Jack inhibitor safety, we've got to think about what disease we're looking at and what the comparator is. And frankly, when the comparator is glucocorticoid, then that's a problem.

And I think we've got to also think that maybe tocilizumab, which is the other currently approved alternative upadacitinib for giant cell arteritis, that there's increasing questions about whether that's doing enough overall to truly suppress the disease, and especially at a vascular level, and whether it will actually truly wash out to prevent as many ischaemic complications and vascular remodeling issues as we might think it might hope it would do otherwise. So really a lot of space there for OOPA. Some really exciting results there. Obviously, I'd like to see the full paper in due course, I'd like to see extension data, I'd like to see structural outcomes and long term safety. But also, I think we're getting to the point that now if we're starting to see more agents, really love to see a head to head between upadisibniv, tocilizumab, maybe secukinumab if it washes out in g Captain.

Plenty plenty more to watch in this space. So plenty more on all of EULA twenty twenty four, roomnow.com.