Virtual EULAR 2020 Round Up - Drs. Artie Kavanaugh And Jack Cush Save

Hey, welcome to UR twenty twenty. This is our virtual roundup wherein we will give you our review of the meeting that just finished last week. Hi, I'm Jack Cush from University of Texas Southwestern Medical School.

I'm Artie Cavanaugh from University of California, San Diego.

And we are coming to you live from our kitchens, living room, wherever we do Zoom meetings these days. In this program, we're going to discuss the abstracts and presentations that we thought were of the greatest interest and most impact from UR twenty twenty last week. Content was chosen without any bias or influence from people we shoot pool with. Artie, it was a virtual meeting, a different experience. What'd you think?

I give you all credit for putting together a virtual meeting in a very short period of time, but it really fell short of trying to emulate the live experience. I think the clearest example of that were the posters. You and I for Roundup love to go to the posters, find a fellow defending their work and talk to them about the work that they've done, the other interpretations that are possible. And here, there was nothing. There was data, there were posters that were shown, but no ability to interact, even though we tried.

We tried to email people. It's just not the same as a live meeting. So we'll see, as ACR is gonna be virtual this year as well, we'll see if this is something that we're all gonna get much better at, but I don't know that it'll replace the actual live meeting.

Yeah, the give and take, educational and social give and take, is really what we missed out on. But also there's sort of a different vibe with the virtual meeting. It's hard to get big time buy in. When you go to, in this case, Frankfurt, or when we go to, should have gone to ACR in Washington, you're committed, you're there. You may have your hub rounds later on, but you got work to do during the day and things to see.

And it's different if people are doing it at home. I think it's more hit and miss sort of drive by kind of education. But let's give people what we thought was important to us. I'm gonna start off with the select choice study. This is the study of head to head monotherapy abatacitinib versus upadacitinib in RA patients who had failed a biologic DMARD prior to this.

So they've been on a number of trials. This is a sort of difficult population, but this is the choice you would make. You fail inhibitor or some biologic, you're gonna choose maybe another MOA or an oral targeted synthetic. They studied two seventy patients. Their primary endpoint was change in DAS28 CRP.

And I think the surprise here was in the results. Actually, did a Twitter poll on this, and I asked people, What would you expect? And they kind of expected that OPA would win, but that they didn't expect much else than that. And in fact, OPA was better in this trial, significantly so in a number of measures, beginning at week twelve, ACR twenty, fifty, seventy, but really at week 26, 24, it was only ACR fifty and seventy that was significant. The DAS 28 CRP was significant.

The CDI was significant, although it didn't look that great. The numbers looked really good, but things that weren't different between the group at week twenty six was the ACR 20, the fatigue score by facet, the pain scores, and Boolean remission was the same. But the real surprise was in the safety. The safety was like, wow, there's much more safety signals with upadacitinib than there was with abatassa. And a few of the bigger ones was hepatic disease, 23 events versus five events, OPA versus ABBA, grade threefour lymphopenia, 45 events versus 26 events.

Opportunistic infections, four versus one, CPK three versus one. There was no difference in zoster or VTE. So the question is, are you more impressed by the efficacy of OOPA or the safety of ABBA?

I think as you said, it's both. And I think, of course, at the end of the day, we want to know which patient. So clearly some patients seem to have done better and certainly have done faster with the JAK inhibitor, but over the longer haul, they both seem to be very effective in a very refractory population. Then the safety, I think with the JAK inhibitor, we've been focused on the zoster, been really interested in the VTE and MACE events. That's not where the differences were.

The differences were more practical sort of issues like lab test changes. And I think that's an important discussion, and that's going come into our choice of what agent do you go to next. In patients like these who have been on a number of other biologic agents, number of conventional synthetics, refractory patient, but this, I think, does give us some good information that we can bring to the patient.

I agree. What did you like?

Well, there's a lot of stuff, actually. I think there was a lot of good material at ULAB this year. One of the studies presented for the first time, although we actually had it presented at the Rheumatology Winter Clinical Symposium, that was the EXCEED study. This is another head to head study. This is in psoriatic arthritis, and it's interesting when you look at head to head studies, our dermatology colleagues are really way ahead of us in psoriasis.

There's about 15 head to head studies, and that's nice because you can then really do a systematic analysis and perhaps actually make comparisons. But we're getting there in psoriatic arthritis. We did have the study last year with ixekizumab compared to adalimumab head to head, where they did a combined outcome, the ACR fifty plus the PASI one hundred, and in large measure, based on the better skin response, they did better. This study was similar, but different. This is aiming at being superior to adalimumab in the joint outcome, in the ACR 20, and head to head secukinumab in a typical dosing, three hundred milligrams loaded, and then every four weeks, adalimumab every two weeks.

The primary endpoint was not met. It was numerically better for the secukinumab, but by the way they did the analysis, and it's little bit complicated because it wasn't a strict ACR20 non responder imputation, which they would have actually won if they had used that. But both worked and both worked very well. As you would expect, the skin was better with the IL-seventeen inhibitor. In fact, when the analyses were done using the outcome that was done in the secukinumab, in the ixekizumab, IL-one mab study, it was similar, it was better.

From both of the studies now, you're starting to see maybe some differences with the safety signals we were talking about for the Select Choice study. So could it be at some point that the IL-seventeen inhibitors and then down the line, the twenty three inhibitors might move up the algorithm treatment of psoriatic arthritis if they are safer? And certainly it seems that they're better for skin. And now we have two studies that show they're actually very good in terms of the musculoskeletal domains.

Yeah, so the interesting thing here was that it was not a positive trial, but it really was no different than the execizumab trial. The difference being that execizumab has a primary endpoint, a co primary endpoint of skin and joints. This had only the joint primary endpoint and then skin as well. And they won on the skin, but they didn't make it on the joint statistically significant wise, but it was numerically better. There were a few other things that were numerically better with the secukinumab.

I think it was a positive trial, although it could be viewed as a negative. I thought that it was just like ixekizumab result. And I think that's, as you say, it's an important result that's going to move the needle forward. And yeah, do think this is interesting that it's another head to head trial. And those are very common, very popular, I think very impactful in the dermatology world.

I'm not so sure that head to head trials in the rheumatology world have yet been all that impactful. Every rheumatologist says, yeah, I wanna see head to head, but will they change their prescribing based on the ACCEED trial or based on the Select Choice trial? I think that remains to be seen.

Yeah, think that it may address some of the biases they have, particularly for the IL-seventeen inhibitors that the musculoskeletal manifestations may not be as robust, but the data would suggest that it really looks like they are across musculoskeletal manifestations.

Yeah. My next one is the BLIS LN or lupus nephritis trial, abstract OP0164. This was a phase three trial of belimumab in patients with renal biopsy proven lupus nephritis, presented by Rich Fury. And I think it's a real win. And there are not enough wins in lupus, and this is one of them.

Why was it a win this time? Why did this belimumab data look better than other belimumab data? I think number one, because it was an organ specific outcome as opposed to trying to get the lupus lead eye two ks, three ks, whatever it takes to get a lupus outcome. They went after a renal outcome, they use a measure of primary efficacy renal response, or PER defined as a urine to protein creatinine ratio of less than 7.7 at week one hundred four. They enrolled four forty eight patients on background therapies, gave them either placebo or belimumab.

And then in the end, belimumab had a forty three percent primary endpoint response to per versus placebo thirty two percent that was significant. Fifty five percent better by odds ratio. Again, it met many other endpoints that they had included in there, the things that you would see in lupus trials, adverse events were the same. I think this is really telling for the way lupus trials probably should go in the future, looking at organ specific outcomes rather than trying to be effective in all domains of lupus, which is not reasonable.

Yeah, I think as you said, the belimumab had sort of gotten the reputation as being kind of rituximab light. And I remember years ago saying that to someone who had worked for the company, and their response was, I said, this is like the Miller Lite of B cell therapies. And their response was, they sell an awful lot of Miller Lite. And that was both the good and the bad, that the effect size across the domains was relatively modest, but the safety was also pretty good. And I think in this study, kudos to the developer.

They rolled the dice and committed to a very large study, which they needed to do, because I think they felt going in that the effect size, if it was there, was going to be small. So they needed to have a lot of people to show convincingly that it was there. They used a standard outcome. Lupus outcomes are a bit of a mess when you think of the by lag, but focused on the kidney. These all make very much sense.

And they picked the PERR, but they also looked at a complete response rate. They looked at renal worsening. They looked at it in a number of ways and it all worked. I think it's an effective agent to be added on, as they, I think, had seen in their other studies, tolerability wise, didn't seem to be much. And that's maybe not unexpected because these are on standard of care therapies.

I think maybe that's the message for lupus and lupus studies. You need a longer time. You need to assess over a longer period of time to really find a difference. You can use standard therapy. I think some of the failed earlier studies, it would have been impossible for them to demonstrate an effect because they just started with gigantic doses of steroids and pulses of cytotoxin.

Here, they used most of the people who were on Cell Sept induction or microphenolene induction, a subset of them, a quarter of them, a year or lupus cyclophosphamide regimen. So there was standard of care there, and they demonstrated a positive result. I have to say, Richie did a great job presenting it. I think you all gave him five minutes, and he went through a ton of data in a small amount of time. Getting back to the idea of a virtual meeting, it sure would have been nice to let him go a little bit more leisurely through that.

But on the other hand, it was on virtual. So I think I watched it three or four times because it was going by so fast with so much information. But a positive study, for sure. My next one, So a favorite study of mine, I think should be of everyone's. I remember know you and I hang around long enough and you keep thinking like oh this new study now it's seventeen years old.

And that's the best study. Best study, truly one of the pivotal studies in rheumatology from way back in the day, early rheumatoid arthritis patients randomized to four different strategies. Was conventional synthetic DMARD switch, conventional synthetic DMARD add on, COBRA, which for the young people was a bizarre ton of steroids sort of regimen that nobody uses anymore. And from the start, a TNF inhibitor, in this case, infliximab and methotrexate. It was testing two things.

One is are those regimens different, but it was also testing treat to target and was one of the earliest and one of the best treat to target studies. And what it showed is that when you do treat to target in a way, all of the groups do well because you keep changing the therapy and they end up on more similar therapies than different therapies. So it showed this, way that the study was done for 10, they were adjusted on this treat to target, and then they were given back to the care of their rheumatologist and followed, and this is now seventeen years of follow-up, And the question is, what is the impact on mortality? And I think that's a fascinating issue because at the end of the day, what do we want our patients to do? We want our patients to survive.

We want this hard tangible outcome, the better survival. We know that active rheumatoid arthritis is a risk for MACE events. Should we be able to avoid that with treat to target? These data look at this after seventeen years, and I think you could say perhaps disappointingly, they say no, that there is still an increase in the cohort in terms of mortality. It was twenty eight percent in the best cohort compared to twenty one percent in the Asian sex adjust population.

So even though we're doing very well in terms of their rheumatoid arthritis, there is still a increased risk of mortality. Now, you'd want to have a lot of comparators. Would this group do better than say rheumatoid arthritis patients who are not treated to target? That would have been nice. They had had a group like that early on, but it sort of fell apart and it's too heterogeneous to be a good comparison.

But I think this says that we think treat a target is going be the answer. And I think it can be an answer. I think it is good, but we can't just say it's over, we won. I think we maybe have to look at other algorithms to do better so that all the patients are in remission or something, because these data would say that maybe we're not doing as great as we thought we would.

Do you think that not showing a major impact in mortality in all the group or all the patients in BEST had to do with them not following treat the target as rigorously as they did in the beginning of the trial?

Because that's a possibility as well. Overall, the group outcomes did look good. It looked like they were doing well. They've shown these data, every year they show the data. And if you look at drug free remission, it's not really high, it's about fifteen percent across the groups, and that's being maintained.

So I think they still are doing well, but that could be, could be that ten years was great and the mortality early on in the first couple of years did seem like it was better. But now, if you look at mortality, you want to look out longer time periods. There was a study from Japan in the Iora cohort presented at EULAR, which sort of said that, no, there's not an excess mortality, but it was early rheumatoid arthritis followed for only five years and didn't correlate it with disease activity. So I don't know if I actually trust that message from that data. But I think we still need to learn about optimal treat to target.

Agreed. Agreed. It still is an unmet need. My next, I think a lot of people really thought this was fabulous, and that was presented by Peter Merkel, OP0011, avacopan in ANCA associated vasculitis. This was an ANCA associated vasculitis clinical trial, three thirty patients where they were on either rituximab or cyclophosphamide, but then were also then randomized to either receive prednisone or avacopan for a year and they followed them.

Avacopan is an oral C5a receptor antagonist. The one year results showed that avacopan and prednisone had similar remission rates and seventy two versus seventy percent. It was the same actually early on in the study actually at week 26 and then again at week 52. And there was overall somewhat less steroid toxicity related to a back pain compared to the other patients. But I wasn't impressed.

I really expected a much better side effect profile than it was there, but there was an advantage there. But I think that the fact that you've got to win without heavy reliance on steroids and ankyl associated vasculitis was thought to be a major step forward. Now, steroids are cheap, Avacopan is not going to be cheap. Maybe we have to wait to get this advantage, but it still is, I think an important finding.

Yeah, and we always like it when mechanistic studies make sense. And this one, you would have anticipated based on what it does that it could work. So it's nice to see that it does. Yeah, the costing is certainly going to be an issue, isn't it? Because it's going to have a utility across some rare orphan diseases even that it may gain approval on, and that's going to make the costing an issue.

But we have a number of patients for whom the steroids do cause problems, as you said, or you really want to try to minimize them to doses that are not going to be tremendously effective, and we don't have a ton of choices for that. I give kudos to the International Collaboration of Rheumatologists who are doing studies in the vasculitides, because they're not super common. You think at each of our institutions or in each of our practices, we'll see a couple of people, and it's much more difficult to do a study in any given site than say lupus, where you can get quite a number of lupus patients, or rheumatoid arthritis, or psoriatic arthritis. These really require international collaboration, agreement on the protocol, and agreement on the evaluations and the conduct of the study. With this and some of the other studies they've done, they've done a real good job of that lately.

These patients are hard to get good data on. Again, it's sort of, as you say, a major accomplishment by the study group to get this done.

So one thing I wanted to cover is the biosimilars. We've talked about them over the past couple of years, a lot of interest, a lot of excitement. It's of course a big difference worldwide in that many countries they have them and they're not even hardly talking about them anymore, meaning that they just accept them. And at EULAR, there were far fewer biosimilar abstracts, 13, which is about a third of what we have seen the past couple of years. And I don't know why that is accepted.

I think that they're so accepted that it's not even that novel anymore. Of course, we have a very different situation in The US. We don't have access to them. We have access to only one, and that is biosimilars of infliximab. And we've seen some published studies this spring saying that their penetrance is really not very great, and we know that, and we've seen that.

And there are reasons for that, and I think we're still not close to the tipping point where we're just assuming, hey, biosimilars, that's part and parcel of what we're gonna practice, as they are in other countries. One thing that is interesting is, and I think it'll be interesting to see how this sorts out, There's the biosimilar infliximab CTP-thirteen, which is approved around the world as a biosimilar of infliximab. And it's given intravenously, lots of studies that show that it's it's as biosimilar as you could want in terms of efficacy, safety, immunogenicity. It's been looked at in a novel way in Europe, and that is as a subcutaneous preparation. Very early on, there was a little bit of interest and very little study of subcutaneous infliximab originator in rheumatoid arthritis, and that's long gone.

They never went anywhere, but the CTP-thirteen manufacturer has done some studies with that in rheumatoid arthritis, and they are getting a favorable opinion from the EMA that says that even though this is not a biosimilar, biosimilar by definition has to be the same route and dose and efficacy needs to be the same. It can't even be better efficacy. The safety might be able to be a little bit better, but this is a completely different. This is subcutaneous versus intravenous. They They've had a couple of studies, they showed the data from the studies which showed that a fixed dose, this is one hundred and twenty milligrams of CTP-thirteen SubQ every two weeks compared to three milligram per kilogram, which is the labeled starting doses around the world, IV, looked like they had efficacy.

What they looked at in a couple of posters at EULAR was the immunogenicity and the impact of weight or BMI index. And it's interesting, they did not find a tremendous effect. Now, the way that the studies were designed, it was a relatively short period of exposure. So a small time to be able to find differences, but some of the concerns that we had had are that subcutaneous forms would be more immunogenic and they didn't find that, and that the fixed subcutaneous dose might in certain diseases not do as well as the weight adjusted intravenous dosing. Again, they didn't find that.

And this is from their PLANET RA study. So it's interesting, this is not a biosimilar pathway in The US. The FDA has clearly said this is a novel biologic agent. But if it is in Europe and other countries look to Europe and it's approved in other countries, a couple of years from now, it'd be interesting to see how all of this sorts out.

Yeah, it certainly is. And the FDA, it's novel in that the FDA considers it not as a biosimilar, outside, away from the way it's usually given and approved for use in The United States. To develop infliximab as a subcutaneous therapy would require a long clinical trial development program. Biosimilar development is an abbreviated program where you basically do one trial and boom, you're done. And then you get all the indications of the parent drug.

Well, again, the parent drugs in The United States are not sub q, so that's why it would never happen in United States. But you wonder if the legislation on that could change just out of practicality based on the data that will accrue in Europe and elsewhere. So it is novel and Renee Wetzkopen was certainly very instructive when I talked to him about this at ACR. I think that the current abstract is equally as impactful. So let's end up with this abstract we both looked at.

It's tofacitinib in systemic sclerosis. What, a JAK inhibitor? That's right, it's Friday or FRI 02/28. This is a novel pilot trial investigator initiated, comes out of Bulgaria and Italy, wherein they enrolled sixty six patients with systemic sclerosis. They randomized them to receive either five milligrams BID of tofacitinib or methotrexate, seven point five to ten milligrams per week as a management for their systemic sclerosis.

Their endpoints were gonna be skin thickness as measured by the typical modified Rodnan Skin Score or MRSS. Then also they use ultrasound to actually measure the thickness of skin at a number of different sites, sort of like the modified Rodnan, but it's an ultrasound skin thickness score. And they also use ultrasound to assess tendon and joints, something called The US 10 SSC score. And the results were surprising. This is a six month trial, an active control trial.

There's no placebo here. And it was significant for tofacitinib with a 50% reduction in the Rodman Skin score. I think it was a 12.5% reduction or something like that for the 12.9% in the ultrasound skin thickness. And then when it came to the joint scores, it looked like it was a significant score. It was like 55%, 56% improvement in ultrasound MSK scores, compared to twelve point five percent in methotrexate.

So these are very encouraging results in a very short trial in a reasonable number, albeit a small number of scleroderma patients. This is the problem with phase two scleroderma trials. They always look great. There's always a tremendous amount of excitement and skin scores can often be the most misleading of clinical outcomes. Nonetheless, this was too impactful and impressive to not present, not put out there.

If anything, we should encourage other tofacitinib and other JAK inhibitors to really aggressively study this. We desperately need something with scleroderma. I want to remind you audience, this is non approved therapy for systemic sclerosis, so don't go there. We really need more experience. But Arty, what was your take on this?

As you said, Jack, very big unmet need and it's really refreshing to see more and more studies on this. The good thing about the more interest and the more studies is it really pushes the outcomes. And there's been a lot of talk, think for how many years, Rodden Skin score, that was it. Scleroderma equals Rodden Skin score. A lot the assessment now of lung function, and that would be interesting to see with a unique therapy such as this.

The ultrasound is fantastic and in theory could be centrally read, could be something that was much more quantifiable. The other outcomes, I'd love to see people really trying to push the envelope and say, We may have more therapies in this condition. We need to know how we're assessing that. We saw that in psoriatic arthritis where the clinical trials really push the need for defining the outcomes, and that's helped the clinical trials as well. So maybe we're seeing a turn of a corner in scleroderma.

Although, as you said, the past is littered with a number of very promising phase two studies that didn't pan out. So hopeful, but you have to keep the past in mind.

There were a few other scleroderma trials here, including others looking at lung outcomes and that looked they were wins because they didn't get any worse. There was also a TGF beta study that was sort of a pilot trial, a little too early for anything, but it's nonetheless exciting to see TGF beta in clinical trials as a target. So anyway, we want to thank the audience. That's it for this edition of UR twenty twenty Virtual Roundup. Please go to the website.

You can get these links. We'll have them linked up on the website. We're going to see you at ACR. On the RheumNow website, you can actually see how we covered RA, PSA, ANCSPA, vasculitis, gout, Still's disease, etcetera. You can go there and check that out.

Arti, thanks for doing this. We'll see everybody at ACR virtually.

Virtually. But we'll see you.

All right, take care now. Okay, so I