Obesity Journal Club: Tuesday Nite Rheumatology Save

Hello everyone. Welcome to Tuesday night rheumatology. We're starting these back up because it's a campaign month and this month our campaign is the obesity imperative. We want to spend the whole month talking about obesity and its major effects as a comorbidity. And as part of this series, we're going to do four weekly webinars here on Tuesday night rheumatology.

Our first one's going to be a journal club. And I'm joined by our two discussants who are highly knowledgeable on both the papers we're going to discuss. I'm going to ask everybody to introduce themselves. I'm Jack Cush from Dallas. Philip, I'm Dr. Philip Mease, a rheumatologist based in Seattle where I direct rheumatology research at Providence Swedish Medical Center and conduct clinical practice at Seattle Rheumatology Associates.

Tom, I'm Dr. Tom Appleton. I'm a rheumatologist in London, get this, Canada, the other London. I'm head of the rheumatology division at Western University in Canada. I conduct clinical research and trials and lead an osteoarthritis program trying to discover DMOADs.

So before we get into our survey and some outline things, I want to ask Tom — because Philip and I, and I like to think I'm like Philip, that we've done many trials over many years in a lot of different areas including trials in osteoarthritis, so we're dabblers — but this is your career. Why have you chosen, or how did you get into choosing osteoarthritis as the focus of your research, teaching, and career?

Well, I mean, first off, I love rheumatology and that's been an incredible love — doing all of rheumatology and getting to learn all there is about the breadth of it. And you know, I think osteoarthritis is a field that has really needed the input of rheumatologists for a very long time. It's had a tremendous amount of input from other experts like rehab experts, like methodologists, like orthopedic surgeons, but you know, as the arthritis experts, truly rheumatologists bring a complementary set of expertise and I think that's so important for this field. So that, plus the fact that it's the largest unmet need in all of musculoskeletal health — to be able to find a medical treatment that actually modifies the disease — is a pretty attractive opportunity I think, and a big gap to try to fill. So I'm just trying to do my part.

And we are certainly glad that you are. Let me go to sharing screen right now. Hopefully I'm going to pull up the right set of slides. Okay, here we are.
thumbs this morning. So um we're going to do journal club today uh where we're going to discuss two articles um and we're going to intersperse that with survey results that um we did in uh yesterday uh and having almost 200 responses. We want to say that this um not only this TNR series but also the whole month of uh of September uh and the campaign on obesity has been supported by Lilly uh and our thanks to them for their interest in medical education uh and spreading the word about the impact of obesity on patients with um inflammatory arthritis, degenerative arthritis, all kinds of arthritis. Uh we think it's uh gigantic and that's why we're doing a campaign where you'll see a lot of content.

Um for the audience, we want you to be an active participant in this program. One uh in the chat box you'll see the links to the two papers that we'll be discussing. Um and uh you can pull those up and refer to those. Uh we encourage your questions and we'll answer them throughout. For that just click on the Q&A box.

And then one more announcement. If you haven't seen today's RheumNow uh in your inbox um Tom has a featured video uh as a feature piece — it's a really good fast I think five seven minute listen about uh osteoarthritis and um the new changes and new thinking. I think it's a really important read that you should look into.

We did a survey yesterday. Uh we had 193 responses from many countries. 91% are rheumatologists. You can see here in blue um 5% are um advanced practice providers. Uh we have a few fellows in there and a few others not like one 2%. And then you know we started off by asking them uh the whole audience have you ever prescribed — and again this email um survey goes out just to rheumatology HCPs, people who are practicing um rheumatology either as a fellow um trainee or rheumatologist. 91% are rheumatologists. We asked all of them have you ever prescribed a weight loss drug um such as the GLP-1 agonist uh and half said no, but 34% said yes, they have and 18% said that they have referred patients to another for treatment with weight loss drugs.

Um I want to ask um our discussants, are you surprised at these results, Tom?

Um, I think I'm becoming less surprised when I hear people saying that they are prescribing. And I think that's really testament to um efforts like this one, like the um obesity campaign, people trying to make obesity much more um a hot topic, not just something we try to move past and get on with uh managing the
inflammatory disease. I think that the trials that we're going to discuss tonight have uh have made an impact on things like that. And I think it's going to change. I think if you asked this question six months ago, it probably would have been much less than that.

So, Philip, you're not only doing the clinical trials in this area, you have been doing teaching in this area. In your travels, have you seen this trend of increasing use or uh or does this surprise you as well?

This does not surprise me. When I asked this question to audiences two years ago, the number of hands that went up would be six. Uh when I am lecturing to the audiences now the number of hands that go up is 40 uh that when I ask the question are you beginning to prescribe these — it doesn't translate automatically into are you successful in prescribing — that's a second step but there's a lot more conversation going on and a lot because I think there's a moral imperative that we have to be addressing this issue now that we're seeing this data coming out about how important addressing obesity is.

Yeah, this is — and bringing up these journal articles uh in this whole month is really about the conversation that needs to happen. Um you know only physicians in general — I don't know a number on rheumatologists but physicians in general who have a patient who's obese in front of them will only a third of the time bring up obesity in some way shape or form. So that's a bit of a concern. So I want to frame this a little more by asking the audience as I did. You have an obese patient with a BMI of 39 who has arthritis, RA, PsA, whatever. And the question was who should initiate treatment for obesity? It should have been who should start the discussion but I wanted to get to something really definitive — writing the prescription. And you can see that um more than half think that it should be done by primary care. But still there's almost 19% of rheumatologists who are willing to take responsibility.

Um but overall 80% of rheumatologists think it should be done by somebody else, not me. And the question — and very few are saying this is the responsibility of the patient. The second question I asked in the same vein is what is the goal of treatment in a patient who has PsA who's obese? The kind of patient who would get into the study we're going to discuss next. You know what is the goal? Is it an arthritis goal or is it a weight or BMI goal? And you can see when it comes to um the answers that it comes to um the
answers that rheumatologist gave — not surprisingly, 46% plus 26%, that's about 72, 73%, are saying it's an arthritis outcome, either MDA or remission. And that only 16% plus 6%, 22%, said that the weight is the goal. And I guess, you know, I gave them a very blatant number of 252, a BMI of 39, but if I gave them very blatant joint counts or skin scores, maybe they would have said more. I obviously both are important, but I want to know from rheumatologists how much are they thinking about weight as the goal here.

Um, Philip, do you want — Jack? I think if you had — if there was the possibility of answering the question with the top two, or even three, but I'd say top two, right? I imagine you would have gotten one of each. You would have gotten arthritis and then you would close second — you would have gotten the 10 to 20% weight loss. That's the failing of my surveys, but it's also the brilliance of my surveys in that I'm forcing them to give me a single best answer, which means you have to — you know, you might have several right answers, but to choose one is harder. And that could be right or could be wrong. I don't know. Tom, what do you think about these data?

Well, I think the same thing could be said actually about your first question — that we could have asked multiple questions. And really, my point is it gets down to what's the intent. Why are you prescribing this GLP in this case, or this weight loss strategy? Is it because you're trying to achieve weight loss? Well, maybe that is a primary care role. Or is it because you're trying to improve cardiometabolic risk? Maybe that's internal medicine's job, or you're trying to target an A1C. There's lots of reasons to prescribe a GLP, and they might all have specialists involved in this particular patient's care. But I think when it comes down to — I'm actually trying to get a better arthritis outcome — I think that's when it becomes essential that the rheumatologist is at least involved in the discussion, if not actually the one owning the script, because the intention now is really focused on the rheumatology problem.

So I have prescribed these newer drugs, but I don't have a weight loss clinic inside my rheumatology practice. Bill, do you think that rheumatologists need to be that much of a weight loss expert — to have a dedicated clinic or do clinical trials — to be knowledgeable or using these drugs?

I think this is going to evolve. At the moment I would say the most
competent care is coming from rheumatology offices where one or more people in the office — either a physician and or an advanced practice practitioner — has taken on some responsibility to really learn about the biology of obesity, some of the issues around safety of the drugs, knowing that if the BMI is over 40 there should at least be a discussion about bariatric surgery and so on. But gradually over time I believe that it's going to become kind of standard practice to prescribe an incretin agent along with our standard immunomodulators as we see the trials coming out, as we're going to discuss in a moment.

And so I think that ironically the level of expertise may come down a little bit as it becomes more common to use this. But I do think that it's really important for people to at least become acquainted deeply with the clinical trial data and to become acquainted deeply with the safety issues so that they can counsel patients on the gradual increase of dosing and that sort of thing.

Yeah. All right. Let's get into the studies. The first paper was published in Arthritis and Rheumatology recently. Philip is the second author on this paper. The TOGETHER PsA study. We featured it on RheumNow when it first got released as the TOGETHER PsO study. And then a few weeks later the TOGETHER PsA study came out. These are — it's a phase 3B randomized open-label multicenter trial with a 52-week duration. The primary endpoint, however, is at 36 weeks. They enrolled patients who had active psoriatic arthritis, and they had to either be overweight with a BMI of 27 to 50 with a weight-related comorbidity, or they needed to just be obese with a BMI of greater than 30.

Patients were randomized — and they were allowed to be on background pain medicines, acetaminophen, non-steroidals; very few, less than 10%, took opioids at any time — and by the way there were no other weight loss drugs or other biologics involved here. They were randomized one to one to receive either ixekizumab, the IL-17 inhibitor, with tirzepatide, and the other half of the group got ixekizumab alone without the tirzepatide. The primary endpoint was a combined endpoint of a high-level arthritis response ACR50 and also achieving at least 10% weight loss at week 36. So you can see that the arms are balanced
balanced here. They use commercially acceptable doses, starting doses and um there was some dose escalation um allowed in this study and these are the results the primary.

And Jack, before going on just to add one comment, um, an important ingredient of all of the incretin trials is there is simultaneous counseling about diet and uh physical exercise. So that is sort of like, even though it's not a pharmaceutical intervention, there is an encouragement that uh whenever you use these drugs they're based on a foundation of also uh good diet and exercise.

Was that like in the STEP 9 that was done at every visit, there was a reminder on that — was that done the same way in the TOGETHR PSA or the TOGETHR PSA?

It was encouraged, yes.

Okay, excellent. Um, the primary endpoint as we said was a combined 9-point ACR50 and 10% weight loss. Um, and you can see on the far left that that was highly significant, 32% on the combo versus only less than 1% on the single drug. I thought more interesting was um what about if you just looked at the arthritis, um, and you know you would expect that um everybody is getting you know ixekizumab here. Um, was there an added value to the GLP-1 agent on top of the IL-17 inhibitor, and it shows that it was significant with an ACR50 of 33% um uh with the combo and 20% with the uh ixekizumab alone. And then if you just look at weight reduction alone, clearly um only the group that got the um the GLP-1 drug had significant weight loss uh of more than 10%, that was almost 85%. The other important thing is that there were many other secondary endpoints in this study that were a clear win for the combination of ixekizumab uh and um uh tirzepatide, and that includes ACR20 — you looking at that, that's sort of grayed out on the box bottom there. These are all very significant: ACR20, minimal disease activity, the PSSI score, the health assessment questionnaire, the HAQ-DI functional outcome, and FACIT um as well as a PSSI 90 score, all achieve significance with the combo.

Um, and the other important thing that I like to look at when it comes to what I think is a combination biologic trial is, is there an added risk when you start combining biologics, because right now there is no FDA approved combined biologic regimen that's out there. I think that this company, other companies, will go for this um combining a weight loss biologic, meaning parenterally administered targeted therapy to uh existing biologic therapy. And in this study the safety outcomes were the same between groups that were the
same between groups, that serious adverse events (SAEs) were lower in the combination group than with the ixekizumab group. There was no mention of SIE — serious infectious events — which was the killer in the combination IL-1 TNF trials from long ago, but they did report opportunistic infections, which was the same if not a tad lower, and there were no other safety signals and no deaths in either arm. Though was there — was there a signal at all as far as the serious infectious events, because it's not in the paper?

No, there wasn't. And also I think the key point is that there was nothing new other than what we already knew about the IL-17 mechanism and the GLP-1 and GIP mechanism. So there — I think the biggest issue is the GI side effects that are common as you're ramping up the dose of the tirzepatide, and we try to avoid that by very gradual increase starting at 2.5 milligrams and then changing every month. That's why the primary endpoint was way out at 36 weeks — it's because it takes a while to get ramped up. But interestingly, 85% of the patients in this trial made it all the way to 15 milligrams, which is the max recommended dose for greatest effectiveness. And I think that that's a testament to both the patients and the investigators that they were able to achieve that degree — of many, many of the patients that I see may pause at lower doses because to avoid some of these side effects.

Yeah. I want to show some time-related phenomena. It looks like the actual separation between placebo and the single arm and the combo arm was as early as week four, and that was maintained going all the way out to week 52, and that was seen both for weight loss and for ACR 50.

Philip, so even though there was minimal weight loss by week four in comparison to what was achieved at week 36, we're already seeing a separation in ACR 50. This is provocative because it makes us think about what beyond simply loss of weight might be going on in the immunology of the incretins in relation to our inflammatory diseases. Yeah, I want to point out all these asterisks indicate statistical significance at very early time points, including week four.

Philip, what other secondary or laboratory outcomes were favoring the combo group? There were a number of them.

So we saw all the usual suspects in psoriatic arthritis trials, like enthesitis being better. We saw that —
we saw that MDA was clearly separated — minimal disease activity achievement, which we consider low disease activity — 23% in the combo group versus a much lower score with ixekizumab alone. And so it was satisfying to see that all of the various clinical domains of psoriatic arthritis were being addressed: skin, joints, enthesitis, and so forth.

Also, many of the patient reported outcomes — pain, fatigue, the quality of life measures — all showed separation. And then importantly, metabolic changes. So there was significant separation in terms of glucose, hemoglobin A1C, cholesterol, triglycerides, systolic and diastolic blood pressure, as well as weight. And so it looks as though many of the types of comorbidities that we associate with psoriatic arthritis — much more so than rheumatoid arthritis — are being addressed in parallel with the weight loss and arthritis improvements.

Um, Tom, do you have any questions or comments on this trial?

Well, one thing that stood out to me as well about that four-week time point is that the percentage of weight loss that happened at four weeks was actually really quite small. In fact, it's probably below the threshold where you would consider that to have a meaningful effect on any of the other features. So, just doubling down on what Philip was saying about this really suggesting there may be additional mechanisms in play. For sure you feel better when you lose weight, but are there other immunologic mechanisms that are in play, or cardiometabolic mechanisms that are in play here, that are actually having an effect on the psoriatic disease itself? And it would be great to see — I think this is also good hypothesis-generating information for subsequent studies.

Yes, I would add to that — everyone is slightly cautious about just coming out and saying, "Oh, this is clearly an immunomodulatory effect." It needs a lot more study, including biomarker analysis, tissue analysis, for us to have a fuller appreciation of that. But when we look at certain translational animal studies as well as human studies, we see a lot of reduction of not only the expected reduction of pro-adipokine inflammatory molecules like leptin, but also a reduction in TNF, a reduction in IL-6, and so forth — which are at least bringing up, as Tom suggests, the hypothesis-generating idea that there could be some immune modulation going on.

Yeah. Um, Phil, do you think that that is suggested at all by the ACR50 only data — that if
you're just looking at the data that if you're just looking at the out out No, I I think if you look at the skin No, I I think if you look at the skin data data Yeah. uh uh uh and that's best shown in Yeah. uh uh uh and that's best shown in the TOGETHER PSO trial that you alluded the TOGETHER PSO trial that you alluded to earlier where there was we saw very to earlier where there was we saw very similar kinds of differences between the similar kinds of differences between the combination arm versus the uh uni arm combination arm versus the uh uni arm and I I think that both skin and the and I I think that both skin and the joints are bringing that question up for joints are bringing that question up for us. us.

Yeah. And so we we we really are uh Yeah. And so we we we really are uh pushing and I know Lilly among amongst pushing and I know Lilly among amongst other companies are really pushing to other companies are really pushing to try to understand this more at a try to understand this more at a biomolecular level. biomolecular level.

Yeah. So let's look at the um the next Yeah. So let's look at the um the next slide which is um really the the um what slide which is um really the the um what I just sort of a summary that you know I just sort of a summary that you know obviously is a big problem you know with obviously is a big problem you know with obesity in the United States. It's 41% obesity in the United States. It's 41% are of a BMI in the United of adults in are of a BMI in the United of adults in the United States have a BMI greater the United States have a BMI greater than 30. But if you include overweight than 30. But if you include overweight with a BMI of 25 or higher at 72%. with a BMI of 25 or higher at 72%.

Um um the end points were easily met Um um the end points were easily met here and strikingly the secondary here and strikingly the secondary endpoints were a multiple win. Uh the endpoints were a multiple win. Uh the strengths of the study was that um strengths of the study was that um combination therapy can be given to combination therapy can be given to these folks without an additional safety these folks without an additional safety concern. Um there was no new safety concern. Um there was no new safety information, no no nothing that that information, no no nothing that that stood out in this trial or the next that stood out in this trial or the next that this is a difficult to treat PsA this is a difficult to treat PsA population where BMI and obesity is a population where BMI and obesity is a major comorbidity. That is I think one major comorbidity. That is I think one of the that's missing from most of the that's missing from most difficult to treat definitions. Um I difficult to treat definitions. Um I think this was strong and that they use think this was strong and that they use a multi-domain outcome. Um and I think a multi-domain outcome. Um and I think it does um help us in some ways uh about it does um help us in some ways uh about the mechanisms of effect here and what's the mechanisms of effect here and what's going on in these folks. But there are going on in these folks. But there are limits to the study. I mean this is an open limits to the study. I mean this is an open label design um that there were um more label design um that there were um more dropouts in the ixie only arm 33% versus dropouts in the ixie only arm 33% versus 15% in the combo arm. There was no 15% in the combo arm. There was no placebo for the tirzepatide treatment. placebo for the tirzepatide treatment. There was a placebo for um uh the There was a placebo for um uh the ixekizumab group if you will. Um and then ixekizumab group if you will. Um and then there were as is the case in many PsA there were as is the case in many PsA trials the amount of psoriasis going in trials the amount of psoriasis going in was modest. Um less than 5% of patients was modest. Um less than 5% of patients had um moderate to severe psoriasis. Um had um moderate to severe psoriasis. Um I'll ask our our panel if do you have I'll ask our our panel if do you have any other main points that you want to any other main points that you want to uh the audience to take away from this? uh the audience to take away from this?

One to me one to mention is the um One to me one to mention is the um abstract that was at EULAR from uh the abstract that was at EULAR from uh the Triveta database Triveta database um a multi-million uh population uh and um a multi-million uh population uh and that they what they found in that study that they what they found in that study was yes this 72% number which was the was yes this 72% number which was the overall population uh that were overall population uh that were overweight and obese but if you looked overweight and obese but if you looked at the PsA population that was 82% at the PsA population that was 82% that were both overweight and obese that were both overweight and obese which underlines the fact that there
is which underlines the fact that there is a genetic proclivity toward obesity, a genetic proclivity toward obesity in the psoriasis and PsA population. So even though they try like crazy to lose weight from diet and exercise, it appears that in many cases having some aid from a medical agent would be helpful.

Yeah. Um, yeah, I think and you know this is an issue as well when it comes to osteoarthritis — we're going to talk about that next — in that there have been a few other reports that say how much of a problem this is in osteoarthritis, and then there are anecdotal reports or small study reports of benefits of GLP-1, and we'll discuss that with the next study. But I want to get to a few —

Oh, one other point I would like to quickly make, Jack, is the fact that when you look at the cellular constituency of visceral fat, it's full of not only fat cells but also macrophages and lymphocytes. And in visceral fat as compared to lean fat, those macrophages and lymphocytes are activated — they have become angry and they're putting out our usual suspects: TNF, IL-6, interferon — and driving inflammation, in addition to the leptin and adipokines that are put out by fat cells. So you've got two pathways of pro-inflammation going on.

I think that's really important. I think that's probably one of the reasons why we might actually hit a bit of a ceiling with our conventional therapies and our biologic therapies in treating patients with PsA. I mean, I'm sure everybody experiences this every day. You get to a point where you can only get so good, and switching from biologic to biologic — switching to a JAK inhibitor — you only get so far with it, and the patient still has unmet symptoms, unresolved symptoms. And part of that could be these leaky visceral fat macrophages that are driving especially innate immune cytokines, and we just don't have a good treatment for that. So this could be a bit of a game changer in that way.

I wanted to ask Philip one quick thing if I could, Jack. Yeah. Um, so I was really interested in the design of this study when it came out and kind of thought, you know, if I was designing this trial the first time around, I probably would have just naively said, all right, let's take people who have been on, let's say, ixekizumab or IL-17 and haven't quite gotten to the best possible state, and then at that point randomize them to going on to GLP-1 or placebo at that point in time, because that
might a little be a little bit more like what I think I might do in practice is adding the GLP or GIP um after we've tried to optimize things with biologics.

So why why was this trial designed this way?

So I first of all I think that we've got multiple trials that are pending uh and you may be already anticipating one of those. But the other point to make is that uh it would probably have required a larger number of patients than were recruited to this trial to achieve a more understandable difference. And so uh there the the patients uh had not failed an IL-17 mechanism but many of the patients had already been on one or two previous biologics TNF inhibitors especially and had inadequate response. So already we're getting into a more difficult to treat population.

Uh more females, higher the the BMI was like uh average was like 38. The uh number of tender and swollen joints. This was a very active population. And so I I think this gave us one of the best chances with an N of 277 uh to see uh the um uh outcomes that we did.

You know, I like Tom's design, but it would kind of get to the question that's already been answered by other studies in um psoriatic disease, and that is if they lose weight, does their disease get better? And that's been pretty well proven, but now you'd be proving it with this intervention specifically as opposed to a specific diet. Um we asked questions of the audience um that pertain to some of the things that we just brought up. Um what is the mechanism basically where obesity results in increased PsA activity um and Philip alluded to adipokine inflammation uh was sort of the runway that most people are tuned into but I think there's more to be learned there about the biology. I'd ask both of you to comment on that. Philip you want to start.

Well again to make the point that uh there's also TNF IL-6 etc that's coming out of the activated macrophages and lymphocytes at that point that I've just uh made. We're going to see I think more biomarker analysis in which we uh are able to document reduction of these all of these pro-inflammatory cytokines but that is yet to come. It's going to come partly from this study but also others uh that are planned for the future. The uh I think it's interesting uh that our rheumatology colleagues already are so much clearly on to this that the importance of of these pro-inflammatory molecules.

Um Tom, in your video today on RheumNow where you talk about um what's going on where you
talk about what's going on with OA, the systemic disease OA, that there are these arms that are weight related and inflammation related. Why don't you get into that?

Yeah, I mean this might be a good dovetail point here between the two conditions and might actually be more shared or overlapping mechanisms among the two conditions and certainly everybody knows that there are lots of people who present with psoriatic arthritis that can look often like osteoarthritis and vice versa in the clinic and sometimes even be hard to tell apart.

Yes, I can attest to that.

Yeah, exactly. Um, the other thing I was going to add here is, you know, there's definitely that visceral adiposity, that visceral fat that we think is coming from the host, but there's also a factor here to be played with the gut microbiome. And the way that our microbiome responds to the foods that we eat, not just how much, but also the types of food that we eat, is also affected by the use of the incretin therapies. And there's a really nice actually osteoarthritis study that's a little bit more pre-clinical mechanistic that's looking at types of metabolites that are released by the microbiome in the presence or absence of incretin therapies and how that changes and how those metabolites can actually act on our tissues themselves. So, you know, there might be a little bit of a host mediated effect like it's the adipokines and things that are released from visceral fat, but there might also be a sort of a host independent effect of changes in the microbiome as well. So, I'm looking forward to seeing more of those studies come out, especially in PsA. I know some of that stuff's in the works.

We also did ask what limits the use of a GLP, GIP weight loss drug with an arthritis biologic and everybody immediately runs to cost, insurance, formulary, you know, that's always the big excuse, the big worry. Um, but how do you guys see this going forward?

Go ahead. Yeah, I thought that the slice for patient reluctance would have been bigger. Um, you know, and maybe it's just because I talk to people about this stuff in the clinic all the time and the number of people who will say, "Oh, you know, my neighbor was on that stuff. I wouldn't try that. I wouldn't be interested in doing that." And it's because of the nausea or the other GI side effects and things that people have heard about. And that's what's talked about, and you all you
about. And all you have to do is just open Facebook or open your newsfeed and you'll see some sort of article about incretins, whether they're good, whether they're bad, and the different side effects and those sorts of things. So everybody's got an opinion about this sort of stuff. So I actually see that as a little bit bigger of a barrier. Philip, what do you usually see?

So I think uh when we open this conversation I would say 90% of our patients are relieved and excited about talking about it because it's been on their minds and they're — we've had, we have a trusting relationship and they want to talk and either they've thought about going on one of these agents or they are already — it's surprising how many times we find, oh, I've just been started on one of these by my internist. So I think there's more receptivity out there than we realize. The big issue uh that has plagued us historically has been insurance shooting us down and saying it needs to come from a PCP or an endocrine or weight loss clinic practice. But I'm already seeing that changing a little bit. The other small point is that because tirzepatide is approved for obstructive sleep apnea improvement, if our patients have that uh it appears to me that we get a little bit better chance if we include that in the application. The other thing uh that I wanted to just comment on is this — and this is again a recent EULAR abstract from Italy uh and they — it was a smaller study and it was just an observational study but what they found was that this isn't an IL-17 combination phenomenon alone; they had patients who were on TNF inhibitors, on JAK inhibitors as well as IL-17s, and upon addition of tirzepatide they had better outcomes.

Uh so it — some people have asked me, oh does it need to be an IL-17? And no, it looks like it's going to be helpful in combination with any of our drugs. Uh Leika Barbosa in Dallas makes a good point. It's a little bit like nutraceuticals and vitamins and whatnot. If you don't ask about this stuff, you may not know that they've already been prescribed either by their primary care or they've been getting it over the internet um through, you know, a dial-in number and telemedicine. Um Philip, what are the general numbers on psoriasis in the United States and how many of those people get psoriatic arthritis?

3.2% of the US citizens get psoriasis or have psoriasis and of those, somewhere between a low percentage of 10 but a more realistic percentage
of but a more realistic percentage of about 30% will have psoriatic arthritis. Right? So these are highly prevalent problems but then again so is osteoarthritis depending on how you slice the pie. Um, you know there's either 32 million in the United States with osteoarthritis or 57 million, you know, um, and then radiographic numbers or autopsy numbers, well I don't even know those.

But this study appeared over a year ago in the New England Journal — um, once weekly semaglutide in patients with OA of the knee and obesity. Again, important study because um knee OA is driven by many factors, not just weight. Um, its mechanical factors, its metabolic factors, and inflammation plays an important but hard to — um, I sort of uh corral and wrangle. Um, data shows that 1% reduction in body weight will improve uh almost by 2% pain, function, and stiffness.

So this trial was designed as a prospective double blind randomized placebo control trial where uh semaglutide um is given uh versus placebo. It was done in multiple countries. Uh it was a 2:1 randomization, more people being put on the GLP-1 drug. Uh and they started at 0.24 and escalated to a target of 2.4 milligrams once weekly. And that was like Philip mentioned in the other trial, that was achieved by 90% of participants. Um and then the other third of the participants received placebo. Both were receiving um counseling on a reduced calorie diet and uh physical activity augmentation and that would occur at each visit.

This was a 68-week trial with a 7-week followup. Uh you had to be an adult with a BMI of greater than 30 to enter the trial. You had to have clinical and radiographic osteoarthritis of the knee with Kellgren-Lawrence grade two or three, meaning not too mild and not end-stage, you know, just right as in Goldilocks. Uh and their pain score had to be 40 or more on a zero to 100 WOMAC scale.

They enrolled 407 knee OA patients. 271 got semaglutide. 136 received placebo. The average age going in was 56. The 82% were women. The mean BMI was 40 and the mean WOMAC was 71 on a 0 to 100 scale. The goal of the study was um the change in body weight at week 68. Uh and the other co-primary endpoint was change in WOMAC pain score. They had other secondary outcomes including clinical function, percentages of weight loss, and uh other things within the um uh like the SF-36 and other important outcomes.

So if we look at — I'll stop there and say Tom, were there any other important considerations about the design of
the trial. The design of the trial. There's a few things and I was even just going to throw in another seven million patients in Canada along to machiners in the US. Of course we're about 10 times smaller than you guys population-wise.

Um yeah I think there's a couple of key features about this. First of all, remember that semaglutide is actually a GLP-1 receptor agonist only. Whereas tirzepatide that we were just talking about is a dual agonist. You've got the GLP-1 receptor agonist and the GIP agonist. So there's a potential difference there. And I think you might see that kind of play out. It's hard to compare these head-to-head, but you may see that in terms of the magnitude of the weight loss effect. So something to just keep in mind there when we look at the results.

The fact that people were 81% women I think is — first of all I think it's a strength of the study. The majority of people with osteoarthritis are women and tend to have worse outcomes and things like that, so it was good to see that actually come through in the demographics here. But the BMI was very high — you know the mean BMI of most of the osteoarthritis population is probably between 32, 32 and a half, something like that — so this is well well north of that. In fact more than 75% of the patients in this trial were above a BMI of 35. So we have to keep that in mind as a bit of a limitation when we look at extending this to the general OA population. Very high BMI in this case and a very high pain threshold, which of course you want going into a clinical trial where you're trying to get a positive result — makes sense, you're trying to enrich your population. But you know WOMAC pain scores — by the way, WOMAC was developed at our center.

That's Western Ontario, right?

That's right. Western Ontario and McMaster. Yeah. Nick Bellamy in the 1980s.

So you know, a WOMAC pain score of 71 is very high — up around the range you would see going into an arthroplasty kind of patient population. So these people had severe osteoarthritis.

Yeah. Most OA trials you need a WOMAC pain score greater than 40 and they're usually a little bit above that in their mean. This is, as you said, very high and surprisingly high. So when you look at the outcomes of the trial, on the left the week 68 mean change in body weight was minus 14% versus minus 3%, and that being highly significant. The graphics show you the percentage of people on the far left who had greater than 5%
weight loss greater than 5%, weight loss greater than 10%, 15%, 20%. So extreme weight loss greater than 20% was still highly significant. Week 68, 22 versus 1%. And then when you look at the pain reductions at week 68 on the right, again on a 100% scale with a mean of 71 going in, they dropped 42 points out of 100, or from a mean of 71 down to 28 or something, with semaglutide. And they dropped 27 points with placebo. Again, everybody's getting something, so you expect a placebo response. And you'll see in the next slide what that looks like on a percentage basis, but they're showing you the number of point drops in those two different groupings on the right bottom graph.

The other important outcome was going to be safety. There were no major safety differences. Serious adverse events were the same really between groups, and the discontinuation was higher with the semaglutide than for placebo, 6.7 versus 3%.

Another way of looking at this data is shown with these changes over time. On the left you're seeing again significant changes at week eight as far as reductions in body weight. And on the right it really seems to get to pain scores — it doesn't seem to happen till after week eight, maybe at week 16 and week 20 where it starts to get really significant. And I'm interested in Tom, what you think about those results. So I'll stop there and Tom, other major considerations on the results and outcomes of the study.

Yeah, there's a few things to look at here for sure. First of all, week 68 feels like a long time. Quite different than the TOGETHR PsA trial that ended at week 36. So you know, you're looking at a 16-week titration period to get up to that maximum dose of 2.4, and then a much longer time on the maximum tolerated dose of semaglutide in the study to get to this endpoint. But if you look at the trend, the primary endpoint sure at week 68 is very very different — it's a huge difference. But if you go through even at week 20, there's clear separation between the groups. Even at week 16, you could say there's probably nominal p values. We can't necessarily claim anything about the statistical significance there. But definite separation much earlier on, and I think this is really encouraging for patients who are looking for an improvement in their symptoms well beyond 15 months out after starting a therapy. So that's
that's point number one. Um, point number two is the magnitude of the effect. So, if you look at the delta between the placebo group and the semaglutide group out at week 68, you're looking at a 14, just over a 14 point difference between placebo and semaglutide. Um, is that clinically meaningful? And the answer to that is yes. So a minimum clinically meaningful difference in WOMAC pain score is somewhere between eight and nine points depending on which studies you read.

Um, and certainly this would be, you know, getting close to the effect size that you would see in some of the average effects after even arthroplasty. So this is a large effect that we're seeing and we haven't seen this before in osteoarthritis trials with medications. It's just we've seen small effects, we've seen maybe small to moderate effects, but this is around a standardized mean difference of about 7 to almost 8.

Um, so you know, for the osteoarthritis field this was a notable, notable improvement. Um, the discontinuations as well — I mean you absolutely would expect there would be some discontinuations due to the GI intolerance, but you know, flip it the other way around, um, over 90% stayed on the therapy. So um, you know, I think overall quite encouraging.

I think that's somewhat of a testament to the fact that although the nausea and either diarrhea or constipation can be very prominent toward the beginning of therapy, as your body gets used to the medicine these side effects tend to dissipate, and I think the testament of that is how many, what high percentages were able to get to the max dose in both of these studies.

That's a great point, and I think it's also coming back to what you were saying earlier, that as you develop more and more skill sets in how to manage the obesity parts of this — whether it's psoriatic or osteoarthritis or other rheumatologic diseases — these principles will extend across, and being able to be reassuring for the patient and have that trust relationship that we'll get through this, we'll go slowly, we'll get to that target together, um, I think can be a really effective strategy.

You know, the study was strong in its design, being blinded and really well done, well-powered. Um, you know, weight loss is a desirable goal in many forms of arthritis and inflammatory arthritis and even in autoimmune and crystal conditions, but I don't think it's as much as PsA and OA. Uh, and this is a very appropriate
and this is a very appropriate study population to come up with a very significant result as they did. Uh again strengthened by having co-primary endpoints — harder to achieve two endpoints at the same time as opposed to a single endpoint. Very high retention rates on the drug, higher with the semaglutide versus the placebo, 87 versus 78. Um it might have been nice with a long trial to have some imaging, but OA — I don't know what to expect in an OA imaging trial especially with plain radiography. It might need five-year outcomes and I don't think that anyone's going to fund that. I don't know that we're any closer to understanding the mechanism of action. Is this pure weight loss leading to clinical benefits, or as we have already intimated, you know, is it the adipokine macrophage effects, anti-inflammatory immunologic benefits that are yet to be really spelled out that could be in play here. Uh I think we'll be seeing more of that in the next uh two years because people are doing trials where they're trying to look at that.

Uh and then the other thing was uh as with the other study, this study um gave instruction on diet and activity but again its role and its impact was not ascertained throughout the study — like what if people were not compliant with that? What if they were compliant with that? Would that have changed any of the results? So um um do any of the panelists want to add to uh the takeaway points in this trial?

I'd like to ask Tom a question. So we know that there are neural effects of these medications. In fact, some people even think that the most prominent — like a recent lecture by Willis Hsu about the really prominent role that the CNS uh plays in the action of GLP-1s. I'm curious about what led to the pain reduction. I mean, I don't think that it could purely have been mechanical, uh or maybe that was only a small part there. We've highlighted the pro-inflammatory nature of its effects in uh potentially in PsA, and the really controlling inflammation uh in a better way. But here it's less clear and I'm curious where you think some of the inputs are coming from for reduction of pain.

I think I really like that hypothesis that there could be a CNS acting or centrally acting mechanism that is actually modifying pain experiences. Um great hypothesis and you know the good thing is in the osteoarthritis field there are people who are expert in being able to ascertain those kinds of effects. Um people like Tuhina Neogi of
effects. Um people like Tuhina Neogi in Boston come to mind, you know really good at separating peripheral nociceptive mechanisms from central nociceptive mechanisms. There may be a role for some fMRI kind of uh analyses and things here but I think all we can do at this point in time is is speculate about that but you're absolutely right GLP-1 receptors are expressed in neural tissues so it's entirely possible there could be some sort of effect there. I guess what we can go back to and you know I wish this trial had included a mediation analysis I wish this trial had included an imaging endpoint as Jack alluded to in fact I wish the TOGETHER PsA trial had included an imaging endpoint uh and we could talk about disease modification.

We're not there yet, but hopefully we'll be able to to get there in uh in subsequent trials. Um but you know, the Shanghai osteoarthritis cohort um was a place where a mediation analysis was done in people who were on GLPs compared to matched patients who were not on GLPs. Uh this was a number of years ago and they actually showed that indeed weight loss itself just the number of kilograms lost does mediate the effect of the semaglutide or a GLP — other GLPs were included in that study — on the WOMAC pain endpoint but only about 30% of the effect was mediated by that so it leaves 65 to 70% of the effect mediated by something else so maybe it's central nerve-acting mechanisms. Maybe it's direct actions on the joint. Maybe it's the peripheral adipokine mechanism. Um all of those things are are interesting and tantalizing hypotheses. But uh but we we just need more data.

You know, um I want to make two comments about this. One, I I I think without a doubt the target organ that um incretin therapy uh has its effect on is the brain. And I think that that I think that's going to be shown undoubtedly across the board um with its many indications and it's in active trials throughout neurology right now including in addiction and Parkinson's and you know other things like other movement disorders. Um the other thing about this particular trial the STEP 9 trial um for years I've wanted someone to give a great lecture on disease modifying therapy for osteoarthritis and we don't have one. We do now. I think this is disease modifying um and I think it is because of many effects which could be on the brain but might be other mechanisms as well.

We had a few more questions to close with. If you have any questions you can put them in um in the Q&A box. We have one
let me see what this is. Oh Philip the question came up. Tom brought up the idea is that um you know uh that you know there's single GLP-1 inhibitors then there's dual inhibitors GLP-1 GIP and now there are triple inhibitors. Do you think that that's going to be a factor in how these drugs are going to be used? Because they're not all equal as far as their weight loss or other outcomes. There is seems to be a hierarchy and these newer double and triple inhibitors seem to be even better. What do you think?

I agree. Uh the data that I've seen so far would be consistent with that — that uh dual and triple mechanisms — I think uh there was a head-to-head between semaglutide and tirzepatide that was published in the New England Journal and it's clear that tirzepatide was superior in that regard.

Uh I don't I don't know enough about the difference in side effect issues to know whether or not there is more. I think my understanding or sense is that they're pretty comparable from an adverse effect point of view.

Uh so uh but we don't have all the data in yet with the triple agent and so I'm — we're waiting to see if it seems even better than the dual agent. Yeah, we've got the um the retatrutide data um at least topline out but not in peer-reviewed format. Uh but Lilly's released their retatrutide data from the TRIUMPH 4 trial and shows very similar uh results to the uh effects that we saw in STEP 9.

Um let's end on this. Katherine Garcia um comments that um she's noticed that fibromyalgia patients on these drugs are also doing better as far as pain and that could speak to the issue we just discussed about neural pathways being affected.

By the way that was supported by a big trietics analysis that was presented at ACR last year and um although there are some flaws in the analysis the direction would suggest that it does benefit fibromyalgia.

And again brings up all this neural stuff that we've just been talking about.

Yeah. Um this final question, obese OA patients, um we asked the rheumatologists who should be eligible for these novel therapies and I must say you rheumatologists are very liberal. Um although a minority of you are prescribing this, a majority — two-thirds — think all overweight patients not just obese patients or obese patients with knees who need surgery or obese patients who have uncontrolled pain. Um, uh, you're saying it's all overweight patients. Um, I doubt it's going to be
that liberal if I doubt it's going to be that liberal if this happens. Um, would either, uh, you like to speculate on where the first indication will be from the FDA and what the rules of use may be in the future. I mean right now you can treat OA, PsA, RA as you want to but if they're eligible for one of these agents either for you know diabetes, cardiovascular risk lowering, weight control or sleep apnea they can go on the drug. So those are the already existing indications.

Um, I just want to speak to the again the concept of having a team, an interdisciplinary team here that is probably going to answer this more broadly. There certainly may be people who uh have symptomatic enough osteoarthritis or psoriatic arthritis to warrant considering uh a GLP and we think that the obesity is standing in the way of them achieving the best possible outcomes. And yeah, rheumatologist probably is going to end up leading the charge there. But there'll be other patients that we're following for their psoriatic arthritis or other other types of rheumatologic disease and they have a cardiometabolic or like was suggested earlier the sleep apnea indication. And so just good communication I think among the specialists among the care providers is going to be really key to get uh to get people onto these medications and um and passing the baton.

I think Philip once you prescribe one of these drugs to one of your patients who else do you get involved?

So sometimes if the patient is open to it I will — a psychologist uh for counseling through — when you think about the combination of PsA, psoriasis, obesity, what does that equal? Depression. And so although a sensitive subject I think as sensitive as discussing weight loss I think mental health uh is an important part of the teamwork. I also uh in some cases do want to engage an endocrinology person who is skillful in this arena. Ironically, in our area, it's really difficult to get in to see an endocrinologist. And so, um, we have to go it alone for a bit, but we — I'll say get on their schedule because I I'd love to have someone looking over our shoulder as we're prescribing these uh uh to bring more skill set uh to the management of obesity in you.

Yeah. I want to um thank our um experts um uh Drs. Appleton and Mi for um their advice and their perspectives um on these two papers. I think it's been immensely um useful for us for those of us who are considering these therapies us who are
considering these therapies and seeing patients. I want to remind the audience that next week Tuesday Night Rheumatology will feature a session — a panel discussion on obesity and inflammation. And on that panel will be Juliana Simonetti, who's an endocrinologist, Lehi Eer from Toronto, a rheumatologist, and Drs. Naveed Sattar and Lee Kaplan, who are endocrinologists, and again they've got — they've researched this area. They're experts on this.

We'll do a survey next week and discuss the many issues coming up next Tuesday night. So with that, I'll conclude our panel and ask each of you to tune in next week for our next TNR. Good night.