ACR24 IL-17 Topic Panel Advancing Care with IL-17 Pathway Insights Save

Hello, and welcome to RheumNow. We're going to be discussing, as a group, the interleukin seventeen inhibitor studies that were presented at ACR twenty twenty four convergence. My name is Doctor. Philip Meese. I'm a rheumatologist based in Seattle, director of the Rheumatology Research Program at Providence Swedish Medical Center and clinical professor at the University of Washington.

I'm joined today by Brian Jaros, who is joining us from Northwestern University, where he is starting off as a bright and energetic faculty person in the rheumatology division there. And so an up and coming rising star to take the place of us oldsters here. And then also by Peter Nash, who I think everyone knows. Peter comes to us from Down Under. He's at the Griffith University School of Medicine in Brisbane.

I've had a chance to visit with Peter there, including this time on the golf course when we were joined by kangaroos. And we have a delightful photograph of me sort of standing near a puzzled looking kangaroo because I was getting in the way of his putting. Okay, so to start us off, let's let's on a more serious note, let's let's get to the IL-seventeen abstracts. And I'll start with Brian, if you want to jump in with choose one of the abstracts, and then I will follow you and then Peter after me.

Excellent. Thanks for having me. And so I'll be first presenting, this was abstract seventeen fifty seven, the in MRI inflammatory structural lesions using a subset of patients from the B Mobile one and two trials. And so as probably a lot of this audience knows, especially after this ACR convergence, bevacizumab is the new monoclonal antibody and it's unique in that it binds both IL-17A as well as IL-17F. And the B mobile one and two studies looked at outcomes of patients with radiographic and non radiographic ankylosing spondylitis and showed clinical efficacy with bemacizumab.

And so this sub study was looking specifically at imaging outcomes of bevacizumab in a group of patients from B mobile one and two who had MRI data at three time points at baseline, at a sixteen week time point, and at a fifty two week time point. And the way that trials were set up is that from zero to sixteen weeks, it was bemekizumab versus placebo. And then at week sixteen, all patients would switch over to the bemekizumab arm. And they used SPARC sacroiliac joint inflammation scores and structural scores to try to objectively characterize using two independent readers, you know, over these time points how inflammation changed. And so they had a good number of people, about around fifty percent of the patients from the trials had enough MRI data to be enrolled.

And the results were pretty at week sixteen. They thought that bacizumab group for non radiographic ANCSPA, almost two thirds of patients had what they called MRI remission, which they characterized by a SPARC SIJ score of less than two and fifty eight percent of patients in the radiographic group. So both groups experienced quite a good response. And that was compared to about a fourth or less of patients in the placebo group. And then when they looked at week 52, the patients who had been on bemecizumab from the start saw even greater incremental gains in remission going all the way up to almost seventy five to eighty percent of patients achieving MRI remission.

And the patients who crossed over from placebo saw a great increase in remission as well, about somewhere between a half to two thirds of patients in the crossover groups achieved MRI remission. And then beyond that, as I mentioned, they looked at structural scores, not just inflammation, but things like erosions or evidence of structural damage. They saw that reductions and erosions were significantly improved in the bemakizumab group compared to the placebo group and also observed again in those who crossed over. So I thought this was a nice additive study to the clinical data that we saw in B Mobile one and two that showed us how this might almost contribute in a, if you want to call disease modifying aspect from an imaging standpoint, and also that by week sixteen, which is a very relatively short period, there were already significant gains in MRI and imaging improvement scores.

That's terrific. So as you know, this drug was just approved about a little over a month ago in The US for use in psoriatic arthritis, as well as both the full spectrum of axial spondyloarthritis. So this is a welcome addition to our armamentarium for agents that can be effective in axial spondyloarthritis. We don't have that many. We've got the TNF class.

We've got the JAK inhibitor class, now the full IL-seventeen class. So this is very important data. And we're going to hear more about bimekizumab in this session as well. But what I'll take on with right now is a new agent that we're just beginning to see data on, and that is called sonolocumab. This is a fascinating drug, which is also an IL-17A and IL-17F inhibitor, so a dual mechanism similar to bimekizumab in that regard.

But it's a nanobody. It's a small molecular entity, 40 kilodaltons, as opposed to the 150 kilodaltons of a standard immunoglobulin like monoclonal antibody. The reason that there's a lot of excitement about nanobody biology is that there is data in humans in oncology studies and also mouse data that suggests that a nanobody construct may have better capability of penetrating into difficult to penetrate tissues. And the perfect example of that is the are cancers, which have are poor may be poorly vascularized and just in general are hard to penetrate therapeutically. So we don't know yet whether that's going to really be the case and be an advantage in treating our conditions, our rheumatologic conditions.

But we have now data from phase two out to twenty four weeks with this medication in psoriatic arthritis patients. So this phase two trial involved three different doses of sunilokumab, our dosing regimens of sunilokumab compared to placebo, and there was also an adalimumab reference arm. There are approximately 40 patients in each of the different arms of the study, and we've seen previously the week 12 data. This was presented at the EULAR meeting, and now we're seeing twenty four week data. And for example, the ACR 50 endpoint, which at week twelve was thirty seven percent of patients achieving this in one of the sonolizumab dose arms, this went up to fifty nine percent at week twenty four.

The other two dose arms had a similar increase, including starting at forty six percent at week twelve and going up to sixty one percent at week twenty four. So really, really high threshold of response. And the other thing that was noted was that the placebo patients who after week twelve went on to sunilokumab were able to achieve fifty four percent achieving ACR50. Other high threshold endpoints included the minimal disease activity achievement, MDA and psoriatic arthritis, are seven items, and if you get at least five of them, then you're in a state of MDA. That's, for example, achieving a tender or swollen joint count of less than or equal to one, an enthesitis score of less than or equal to one, a PASI score of less than or equal to one, as well as patient global, patient pain, and so forth.

So at week 12 in sonolichomibone of the sonolichomibor arms, that was achieved in forty four percent of patients already. This was pretty high for achievement of this. We've often historically seen levels like thirty percent of patients achieving an MDA response. And then at week 24, this went up to sixty two percent, so quite a high achievement of minimal disease activity. They also assessed an interesting combination of achieving an ACR 70 response and a PASI 100 response, so complete clearance of skin and a very high threshold joint response.

And one of the sonolizumab arms went up to forty eight percent on that particular dual outcome measure. So this is looking like a promising addition. It's also an IL-17A and F dual inhibitor. Safety signals were similar to what we've seen with other IL-seventeen inhibitors, including an occasional case of oral thrush, but in general quite well tolerated. This is now proceeding into phase three.

Peter, do you have any comments about this particular approach?

Look, it looks very interesting and begs the question, if it smells like a 17 and tastes like a 17 and does like a 17, you've now got five of them, six of them, seven of them if you include the Russian one and whatever. How many do we need, Philip? And I think that the key question is how do we pick up amongst them all? And what advantages one have over the other? And do they have less adverse effects or more adverse effects?

And we're desperately looking for evidence that blocking F is superior to just blocking A. And that was the abstract that I was going to talk about, if you wouldn't mind that where we have common clinical problem doing very well on seventeen for a long period of time and then into current infection or something and they flare. And do you change class or do you switch within class? And the Canadians from four institutions looked at a multi centre retrospective review, only a small number of patients, forty three. But they had prior exposure to Secu, ICSI and Bredalumab, which we don't have because of the background of depression issues that was never approved in our country.

And the reason for discontinuation was mainly in effect, in efficacy over time. So, they switched to bimekizumab and within four weeks, or by week sixteen, they'd picked up PASI 100 in sixty three percent of them, PASI 90 in eighty four percent, and IGA zero at ninety six percent. So, there's some evidence that switching within class and adding F inhibition might be an advantage in that group of patients. And they did look at the bimekizumab radiant study, which was open label and the same issue. Sex switched to Bime for whatever reason, they picked up good response, particularly skin response over time.

So I'm just looking for ways to try and pick amongst the five different IL-seventy inhibitors and, whether there's a big advantage blocking F, whether there's a big advantage going as a nanobody. And I think we'll never get head to head really. So we're going to have to decide based on, this kind of data. Over to you, Colin.

So one of the things that we are going to see in the future, there's a study known as B BOLD that is just launching, which is comparing bimekizumab with the interleukin twenty three inhibitor risankizumab, also known as SKYRIZI. You have

any started that trial as well.

So you all are participating. Oh, cool. So any comments or thoughts about that as that goes forward?

I think it's very important because the safety of the 17s and 23s are remarkable. They're starting to be used in combinations. The skin efficacy is fantastic. The joints, you know, one has a bit of axial, the other has a bit of IBD. There's always a tiny wrinkle.

But how do we pick amongst all these fantastic new agents when we don't have head to heads? And I think it's a very important study from a strategic point of view to know which to pick. And the only other abstract I was going to mention came from Czechoslovakia where they asked the question if you'd failed the TNF, which everyone's being pushed into because of biosimilars in the rest of the world, not so much where you live, but, in UK, in Europe, the biosimilar TNFs are being demanded by NICE and other regulators. And if you fail that first TNF, where should you go? Another TNF or a 17?

And these guys looked at 127 patients and followed them and found that there was very little difference in retention between the two. And there was only minor differences in disease activity improvement between the two, but the 17s were much safer. They had half as many serious adverse events. They had half as many AEs in general. So, like you and I have been saying for a long time, we're used to starting a TNF, but you can't show a difference in efficacy, whether it's spirit head to head, whether it's XSEED, whether it's the SURPASS in the spine.

So, efficacy is the same, but the safety is very different. And so which should you use first Philip, TNF or seventeen? Either in TSA or AXPA?

Well, oftentimes some of my patients will say, Boy, I've heard this story from you about efficacy and safety. It sure sounds like we should start an IL-seventeen because of the safety. And I'll say, Well, sorry, the formulary manager is going to push us in the direction of it, Tina. And they're going, What? Oh, well.

All right. Brian, do you have a second abstract for us

Doctor. Yeah, piggybacking do off that exact topic. This was looking at a similar question to the abstract Peter was just mentioning, except this was from the core Avitas registry of PSA and SPA. And this was, again, after these patients were started on a first TNF that was then discontinued due to clinical inefficacy. Does cycling to a different TNF or switching to, this was specifically IL-17A inhibitors, is there a difference in outcome between patients?

And so the group looked at this registry again, both psoriatic arthritis and axial spondyloarthritis and stratified them kind of into two cohorts, analyzed them separately and used our major kind of outcome metrics, the BazDi for the axial spondyloarthritis group and CDAPSA for the psoriatic arthritis group, and look to see in those that were cycled to a TNF versus an IL-seventeen if there was a major difference between the two. And the short answer to that was no. They had similar primary outcomes between the groups. They were actually numerically higher in the did better in IL-seventeen groups, but not meeting statistical significance. But interestingly, a few of the secondary outcomes did meet significance favoring the IL-seventeen group, and that was patient reported fatigue actually in the axial spondyloarthritis group was significantly improved with the IL-seventeen inhibitors, and the physician global assessment of arthritis and psoriasis in the psoriatic group was also significantly improved in the IL-seventeen switchers compared to those that stayed on the TNF.

And so again, I think I'm not sure where you know, these outside of the limitations of insurance and those dictations where these fall in our armamentarium. I think it would be an interesting question. I don't know if this has been looked at. You know, in practice, I feel like we often try to differentiate primary versus secondary failure of a TNF to know if we should class switch. You know, did they ever have an adequate response that then petered out or were they never responding from the beginning?

And I wonder if we have the numbers or, you know, in these registries or groups to power, you know, looking at primary versus secondary failures and seeing if there's a more meaningful difference between those.

Sure. And of course, we need to take some of this with a grain of salt since this is registry data as opposed to clinical trial data. But love the way you said they, So it's mainly Alexis Ogden and I that are doing the Core Evitas Registry. So I've been the scientific director of it since 2013. And what we try like crazy to get investigators to try to write down or mark off why they are changing therapies, but it's like pulling teeth to get them to really give us the full answer.

And sometimes it's not clear. Sometimes it's efficacy, sometimes safety, sometimes it's administrative related to whether or not they can get the drug covered. But I think the CORE Evitos Registry really does a good job of collecting efficacy and safety data. So we collect all of the major outcomes that we do in a clinical trial, and we try to have well adjudicated, especially serious adverse events in the registry. So I think it's a pretty good one to get learning from.

I think if we just had a greater N, we would have seen statistical significance. So just saying. So I'm going to follow with one important abstract that was presented at the meeting, and this had to do with safety of bimekizumab. Because this drug had been it took a long time and various issues that led to a delay in approval by the FDA in getting it into The United States. We have out to two years of full safety data from the pooled phase 2b and three studies in both psoriatic arthritis and axial spondyloarthritis.

So a huge data set, a total of eight forty eight patients in the axSpA studies and a total of fourteen oh nine in the PSA studies for a total patient year experience of two thousand five hundred in the axSpA axSpA arm and three thousand six hundred and fifty five in PSA. It's unusual for us to have that much safety data right at the time that a drug is approved in PSA and axSpA. So what we have is here are some of the factoids from that review. Number one, the incidence rate for serious infection was one point four in the axSpA group one point three in patients with PSA. I think these are good numbers.

For example, if you don'tif you have axSpA or PSA patients without any treatment at all, the background rate of serious infection is likely to be hover around one event per one hundred patient years, so this isn't that much more than that. Although this is not head to head, and it's hard to do a comparison, these rates are a little bit less than what we've seen with some of the other mechanisms that we use for treating PSA and axSpA. There was a signal for candida. That's not a surprise since IL-seventeen as a cytokine helps protect us from surface candida, and so we saw some oral thrush. For the most part, this occurred once in the patients who experienced it.

And then that was the great majority. A handful went on to have two, three, four episodes. Usually these were mild to moderate, easily treated with topical nystatin, or sometimes diflucan. So this is an issue that we need to think about and maybe advise our patients about the possibility of it, but generally reasonably tolerated. And there were no systemic fungal infections.

That's a key point, because as you know, with the TNF inhibitors, we sometimes see systemic fungus like histoplasmosis or coccidioidomycosis. Permanent discontinuation of bimekizumab was unusual for any adverse effect reasons. There were cases of inflammatory bowel disease. This is something that we know occurs as a class with IL-seventeen inhibition, and some of these were new onset. In the clinical trials, patients with active IBD were not allowed to participate, but you could have a history of IBD, and some of these cases were flares of previously known Crohn's disease or ulcerative colitis.

So that too is a rare but important issue for us to be aware of. Otherwise, we didn't see a signal for adverse cardiovascular events, malignancy. So, by and large, this was similar to the safety record that we've seen with other IL-seventeen agents, and I think it's a pretty tolerable one. And if, you know, sometimes we get into using what I call dual therapy, like, for example, if I've got a patient with a really problematic case, I will sometimes put two biologics together. And so I think this enters into the class of agents that has a really pretty good safety profile that I would not mind using as a dual therapy.

Thoughts, you all, about safety factors?

I think they're very safe, the 17s in comparison. For example, you're quoting one point seven of 100 patient years, the TNFs, particularly in rheumatoid, where they're more likely to be on a little bit of steroid, a little bit of methotrexate, was three to four per one hundred patient years. So that means if I treat one hundred rheumatoid for a year, I'll put, sorry, if I treat 25 rheumatoid for a year, I'll put one in hospital with a serious adverse event, usually infection. So we just take that risk on behalf of our patients. And it does drop off over time, but it's a different class.

I came across, you're asking about 17 versus 23. I found abstract 2,585, Stefan Siebert's abstract, where he took 600 people from the PSA bio observational study who started GUS or who started at 17. So, the 23 or the 17 and they used from baseline to six months. And there was no difference in the minimal clinically significant difference. So, you know, the two very safe classes.

It's nice to see Bemi the AF. China's got an AF now. There's an AF nanobody. So we just, we're going to have a plentiful supply of 17s and I just don't know how we're going to pick amongst them unless there's an advantage. Bemi has strong numbers post TNFIR, stronger than the others, but it's, you know, it tastes like a 17, smells like a 17, it works like a 17.

So, one do we pick, Phillip?

I'm gonna leave that to you, Peter, and your unique situation in Brisbane. So Brian, let me give you a couple of cases. Both of these are individuals where they have PSA, they've had a history of some diarrhea occasionally, no bloody diarrhea. So we ended up recently with such patients testing fecal calprotectin. In one case, it was nearly zero, but in the other case, it was one hundred and sixty two.

So how would you have handled these two cases with respect to the class of drugs that we're considering today?

Yeah. So, I mean, I'm much more reassured than the patient with the lower undetectable calprotective, common things being common, you know, there's probably a host of other reasons to have diarrhea. And if there's without red flag symptoms and the inflammation is normal, I don't think that would, that in particular, would deter me from using an IL-seventeen, for example, in that patient. The other patient would make me nervous. I feel like that's the flip side or the benefit, I suppose, of having a a number of different agents that, again, maybe have slightly different risk profiles but don't necessarily have head to head data suggesting that one is completely superior to the other in in all patients.

And so until that individual kinda underwent GI workup for, you know, colonoscopy, etcetera, I think I would probably on the side of caution and avoid a 17 knowing that there's other classes that, you know, could probably appropriately treat things up front. So,

you'll be happy to know just that a comment, Peter, this patient is now scheduled for a colonoscopy in the middle of December, so we'll see. Peter?

Well, was just gonna say that our gastroes teach us that the fecal calprotectin, if it's a week to ten days off an NSAID, is a very sensitive cheap test for gut inflammation. And they've actually told us that under 50 rules out active inflammatory bowel disease and over one hundred fifty needs a colonoscopy because although it might be IBD, it could also be bleeding polyps and malignancy, etcetera, etcetera. So they've given us those two numbers. One hundred fifty do something. If it's higher, fifty be reassured that it's not active inflammation, often NSAID.

And we don't screen everybody. We only do people with symptoms. And it can be very helpful, like you were saying.

Good. So I'm glad to hear that, that there is some similarity in this. We're sort of new to testing fecal calprotectin. I haven't done this a lot, but in our setting, I'm coupled with a gastroenterologist who really is, he's been participating with us in teaching, visiting physicians who go through a preceptorship where we teach them about PSA and AXPON. He's been coming in and teaching us about IBD.

So it's really been neat to reach across the aisle and learn from the gastroenterologists just in the same way that we've been doing that with the dermatologists for many years. I'm curious, do either of you all have any comments about uveitis? There was a single row in the large safety database with bimekizumab where it appeared that the frequency of uveitis episodes in patients with a history of uveitis was less in the bimekizumab arm than in the placebo arm. But I know with the IL-17A inhibitors historically there hasn't we don't think it harms and causes uveitis, but we're not sure if it helps. Peter, do you have any comment about uveitis?

I've always thought uveitis and the 17s are neutral. They don't help, they don't hurt, they don't prevent it. And if you've got uveitis, that's a TNF indication. But I can't help feeling that it's like, you're only putting people into trials of 17s now when it's the third, fourth, who have no uveitis issue. And even then, it's only three per one hundred per year get uveitis.

So, we're really talking about small numbers. And if you follow people for twenty four weeks, even a few 100 people, etcetera, you're not going to see a lot of uveitis. I So, can't help thinking it's a little bit of selection bias going into the trial, low risk of uveitis because of seventeen's history. But they did have lesser than you'd expect. The other 17s have done formal trials in uveitis and have been unsuccessful.

I think Bemi is doing a formal trial to try and answer that question as well.

Terrific. Do any of you all have parting comments before we wrap up our session today?

You can go first, Brian.

Yeah. No. I I'm excited about I mean, it's for me, like, I am excited to be entering and starting my rheumatology career in this kind of, like, pharmaceutical boom. I feel like we've been in and is continuing at a very rapid pace. So, it's a very exciting time to be having discussions like this where we have, I guess you call the privilege of the conversation is like, agent do we use and not like, do we have an agent to use?

So, in a way, I kind of view it as maybe a good problem to have, if you will. And I think it's exciting that we, like each ACR, each convergence, we keep hearing about these new agents that can potentially help our patients even more.

So, tend to think that this class has a safety advantage and they should be used early in the treatment algorithm. But Philip, you and I and Brian, we have those difficult to treat PSAs separate to the complex to manage that GREP is trying to sort out. And it's in the difficult to treat the non responder, who I wish would be a little bit more scientific no matter which seventeen inhibitor we use, where we might actually measure a trough level and see if, you know, there's some issue with compliance or, Fc fragment being chewed up by antibodies, or in fact they've got a trough dead smack in the middle of where it should be and they're not responding, should switch class because we're so lazy, we just have so much choice, we just flick to another drug And do that for six months and then flick to another drug for six months. It's just, it's a shame we're not a little bit more scientific about the way we use our biologics. The responder, no problem.

It's that non responder group that, you know, you and I all get sort of tertiary referrals now of someone who's failed five biologics. And you ask yourself, did they actually fail each of those or just take it on the word of the patient and the treating doc that that's what happened and try and find some other class of drug. I think it's a shame that we weren't like the gastro's who were stuck with two biologics for so long that they started using levels to make sure they got every ounce of juice out of each one.

Yeah. Good points, both of you. So I'm excited about the fact that even though there are a lot, it's good to have more, because I think we do run into the problem of people running out of gas with one agent and do finding some ability to have benefit from another one. So the Canadian study that you presented, Peter, I thought was very useful to teach us a little bit about that, small numbers, but nonetheless, some optimism that switching within the class can be helpful. I think it's going to be good to have this extra oomph, so to speak, from inhibiting both A and F, and maybe getting a little bit better efficacy on certain domains, as well as having a little bit more durability.

So I want to thank the listeners that are attending this Room Now podcast to learn more about what was presented at the ACR twenty twenty four convergence and our little team's efforts to teach you more about the interleukin 17 class, especially in PSA and AXPA. So thank you very much for attending.

Thanks, Philip.

Thank you.