New, Advanced Therapies in Gout Save

Hello everyone. Welcome to Tuesday night rheumatology. This is our fourth and final installment on gout. Tonight we're going to talk about new and advanced therapies in gout. I'm Jack Cush, RheumNow. I'm joined by a panel of experts — the people who not only did guidelines but did the trials and do most of the teaching on the drugs that we'd like to know more about, and that's what we're going to talk about tonight. I'm going to begin by asking them to introduce themselves. Let's start with Naomi.

Uh hi everyone, good evening. Uh I'm Naomi Schlesinger, a goutologist trained with the number one gout expert Dr. Schumacher as a fellow and have been in the field for many years.

Excellent. Herb, uh Herb Baraf. I uh was formerly in private practice with Arthritis and Rheumatism Associates in the DC area and now do some teaching at the NIH. And I've been involved with gout ever since my first research project as a fellow looking at the effects of moonshine on gout. [laughter]

And uh I'm delighted. We won't go into why you signed up for that, Dr. Baraf, but um it's interesting nonetheless. And look at these little bottles.

And Ken, hi Ken Saag, director of clinical immunology and rheumatology at the University of Alabama at Birmingham. Interestingly, Herb, it was actually Eugene Ball at University of Alabama at Birmingham that described saturine gout in moonshine uh many many years ago. Uh so we see some really bad gout down here in the south.

That's wonderful. They're being visited. We commiserated.

All right. So, uh let's go to um slides that we'll use uh our template for this evening. Um here we go. Boom. Right there. I'm going to go to full screen. I want to uh first recognize that this month uh on gout and education on gout has been rich in content. Uh and we want to thank uh the support of Sobi um throughout the month in making sure that we bring you only the the best in written content, videos, uh podcasts. It's really been an incredibly rich week. We want to thank you, the audience, for um signing up and coming on for this fourth and final program where we're going to discuss new and advanced therapies in gout. I want to encourage you to ask questions of our panelists throughout the evening. Um uh use that by clicking on the Q&A box. Um we'll see your question and we'll address it uh in this session. Um I think that's it for the housekeeping. Uh get a glass of wine, a cup of coffee.

Uh you know, what we do prior to these Tuesday night rheumatology sessions is we send out a one-time only email invite to rheumatologists asking you to answer one gout question and then you find out oh there's eight more after that. Uh we want to thank 274 of you who answered this survey with little or no notice and note that again 39 countries, two-thirds are from the United States, uh 93% were rheumatologists and two or 3% were fellows or advanced practice providers.

Um, I want to begin by saying that I'm writing a piece right now either for tomorrow or the next day about four decades of gout development and management. And uh, it actually begins with a survey that Jim Fries did back in 1988 on what was important in rheumatology. And I repeated that survey in 2008, 2016, and just recently. But anyway, when you look at gout and its development, you know, we have these early eras which were really focused on um gout flares and what drugs you used, and back then it was urate lowering therapy — but are you an overproducer or underexcreter — um and then in 2020 it was treat to target uh and the development of new drugs including not just febuxostat but our first biologic which was pegloticase and then others, and then imaging became the big issue, and really like in the last 10 years it has been about advanced therapy and biologics and drug development, and that's what we're going to discuss tonight with these folks who were involved in the clinical trials and involved in how these drugs will be used.

Um so let's begin with a first question to our almost 300 rheumatologists and I asked them which biologic is FDA approved for gout, and um there were actually two right answers here — that's sort of a no no in the rules but I can break the rule since I sent it out. Uh the right answers here are pegloticase and canakinumab. Uh 51% said pegloticase — and you could only choose one on these survey questions — and 22% said canakinumab, but 20% believe that anakinra is — maybe it should be, but it is not — um and you know tocilizumab is a pipe dream and we maybe can talk about whether that belongs on the list for the future, but the right answers here were uh pegloticase being approved in September 2010 uh with the indication being that uh it is indicated for chronic gout in adult patients refractory to conventional therapy — kind of a broad indication if you will for a drug, especially a drug that's not being used enough right now — and then canakinumab —

Oh, someone's got to mute themselves.

— canakinumab
was approved in August 2023 and here the indication was in patients who could not take colchicine or non-steroidals either because of intolerance or other reasons. And it was also — I guess that's the main — and for gout flares being the other indication. So anyway, let's start with Ken. Ken, are you surprised at all by any of these answers? Turn on your mic. Yeah.

So I think the the anakinra data, Jack, or the anakinra response is curious. And you know, I was involved with the ANIGO study where we did a head-to-head of anakinra versus triamcinolone. It was designed identically to the study that led to the approval of canakinumab and regrettably it didn't lead to an approval. The reason is that it was not superior, in contrast to what we saw with canakinumab, but it looked very much non-inferior to triamcinolone and all the secondary endpoints for the most part tended to favor anakinra. I will tell you that in a tertiary care academic center we use a good bit of anakinra, particularly on the inpatient side when we're dealing with critically ill patients in whom glucocorticoids, NSAIDs, and colchicine are relatively if not absolutely contraindicated. So it is the drug that we're using and I think you're seeing that it's off label but it is used.

Naomi, how do you feel about IL-1 inhibition in general? Yes. So I guess I will tell you why canakinumab is approved, because we actually finished conducting the studies and I presented this at the ACR in 2011, 2010, 2012, and it wasn't approved by the FDA, so Dr. Schlesinger wrote a letter to the FDA and two years later it's approved by the FDA but only for acute flares, not for prophylaxis. When the studies were done, prophylaxis was beneficial when using rilonacept and canakinumab, but neither is approved for prophylaxis. And canakinumab, as Ken alluded to, was approved compared to 40 milligrams of triamcinolone IM, which in the European countries is the dose given for acute flares — hence why we chose that dose as a comparator.

So that happened with rilonacept too. They did their trials to use the inhibitor as prophylaxis with the initiation of urate-lowering therapy but did not get approved. What do you think about that? Should these drugs be used for that reason or just for flares?

Well, I was involved with the rilonacept trial and it wasn't successful, but as a practical matter, canakinumab is great for prophylaxis and anakinra is great for an acute flare refractory to standard therapy. So it's all backwards and upside down. And canakinumab is exceptionally expensive, and anakinra — if you buy a week's worth and give a patient 100 milligrams daily for 3 days and put the rest in the fridge — the patient can probably treat two more flares after the first one should they have another refractory flare. So these drugs are effective and probably more effective than standard therapies, although they're usually not brought out until standard therapies fail. And I think in general canakinumab is too damn expensive to be used for acute gout flares, although the tail of the drug is good for three or four months — you get a very nice sustained degree of suppression.

So that was canakinumab you're talking about there. Canakinumab. Yeah.

And when — to any of you — when you use anakinra in acute gout, do you use that in addition to a non-steroidal or colchicine at the same time, or in place of? I mean, if you have to — [laughter] — usually it's in place of; it's usually in somebody that has a contraindication or has failed the other stuff. Sometimes we use a combo of things in people that are really rip-roaring, and that would be one way to do it certainly. You know, it's not totally innocuous. There are infectious risks. I think we feel like IL-1 inhibition is safer in many ways than other things we do. And obviously we don't have the large-scale RCTs to look at safety signals adequately. But I don't think we should ignore that potential concern.

Yeah. Although in Ken — and canakinumab for instance — there's data of over 10,000 patients and really there are no serious infections, as opposed to TNF inhibitors. Yeah, I'd like to add though that for acute flares, remember that patients have kidney disease, they may have liver disease, and I don't use so much colchicine for acute flares. I don't use NSAIDs for acute flares, but rather corticosteroids for acute flares. You know, I think we're usually seeing these people fairly late. And I think it was discussed last week — you use a drug like colchicine, it's great in the first 6 to 12 hours, but beyond that it's not a particularly effective drug for a patient with a flare. When a flare drags on, you need something a lot stronger than colchicine. Although if you look at the GRADE trial, their primary endpoint was 50% reduction at 24 hours — only 37% get to that. So almost 70%. Yeah. Well, but the trial —
didn't allow initiate. You had to call into a call center and the treatment had to start within 12 hours of the onset of the flare, which is all right. You guys are talking about a trial that we know nothing about. The AGREE [laughter] trial. All right. Yeah. So, so the AGREE trial, that's an interesting study because that was the study that led to the approval of colchicine. Keep in mind that colchicine was the drug that's so old that it was being used before the FDA even approved drugs. And through a loophole in FDA legislation, a company came along and actually marketed it. It went from pennies a day to a very exceptional price for a while, um, based on that work. The good news is the AGREE trial was the study that actually showed its efficacy and showed that you didn't need to give it every two hours like they used to say in the Washington Manual, or until the person got diarrhea, but that you could use it just a few times a day at most and you would have similar efficacy and less toxicity. In fact, it was Benjamin Franklin that first approved colchicine in the United States, but that's a whole other story. Yeah. And interestingly, it's approved by the FDA for prophylaxis based on historical data. So it was not in a randomized control trial. So it's actually very interesting as Dr. Saag alluded to.

Okay, let's go on to our next question. Um, here we're going to say what is the indication for IL-1 inhibitor use in gout? You can see by their answers, they're a little bit all over the map, especially since there's only one IL-1 inhibitor FDA approved. The lead answer was if NSAIDs or colchicine is contraindicated. That's 40%. Acute gout flares, that's right, at 29%. So those two — you know, that's almost 70% — people got it right. Um, only severe gout flares, that's not in the language. It doesn't have to be particularly severe or horrific. Um, as part of ULT initiation for prophylaxis — that was in the cloud of trial designs but has never made it to be an FDA approval. And I don't know what the last little sliver answer was, but I think that most of us are probably okay with that. Anybody want to modify this at all as far as a good reason to use an IL-1 inhibitor other than gout flares — can't use the other drugs, the other drugs don't work well?

And so, Jack, it gets to the issue of what Herb raised earlier. I mean, these drugs work well, but they've got to be given parenterally, which patients don't really like that much, and they're very expensive. And anakinra is off-label, so you've got to hassle with the insurance company to get it. Um, you know, there's a lot of investigation now looking at oral inhibitors of IL-1 and NLRP3 and inflammasome. And I think that could be a very exciting area for us down the road if we had an oral agent that was efficacious.

Now the other thing to note, and I think this has been alluded to as well, is it's really difficult to do studies of acute gout flares. You know, these occur in the middle of the night, on the weekends. The studies take forever to enroll. They're messy. It's been a real challenge in terms of getting regulatory approval due to the difficulties. And the other problem I think we've run into is sometimes these studies are done by non-specialists who may be including some people in the studies that don't even have gout, which is really disturbing, but may attenuate the studies towards the null hypothesis.

The beauty of the AGREE trial is that patients were screened who had a history of gout and went home with the drug but were told not to take the drug, and at the first inkling of a gout flare they called a call center and there were a series of questions that were posed, and if the questions met criteria they could start the drug. Every other acute gout flares trial that I've been involved with requires that the patient show up in the office. And I think, Herb, that is exactly the strategy that's needed. In fact, you could imagine where you could give somebody a lock box with a code, and you call into the call center, you're having a flare, you meet the criteria, and they give you the code to open it up and start the drug, and then you can actually track utilization. So that's really the strategy going forward for sure.

Yeah. And that trial — the company was roundly condemned because of the price they placed on Colcrys. It was about 50 times more than colchicine — you know, prior to its approval it was a couple of pennies — but the study was exceptionally well done and taught us a lot about the use of the drug. Have we beaten this horse enough, Jack? No. No, we can beat this forever.

I got two questions. Um, Luis Torigroso — hey Luis, I saw you last week at the Florida Society of Rheumatology meeting — asks what percentage of gout flares are refractory to standard therapy, colchicine and non-steroidals, so that you would consider an IL-1 dose —
anybody have a a number there you know I can't give you a number I wish I could I will tell you that you know you take some of these people that have chronic gout they have it's a chronic arthritis. They have flares constantly. They have tophi. They're ulcerated. They're in the hospital infected. Um they're flaring. We're not sure if they're septic or if they've got gout. These are the some of the people we're dealing with and it's just a real mess. Um so yeah, so we try what we can to try to settle them down and and it often does pull in an IL-1 inhibitor. Um often again because more of a contraindication than lack of efficacy of the other things. I think if you give enough a high enough dose of glucocorticoids, you probably can settle a flare down, but the toxicity is going to be there for sure.

Is the timing the timing of therapy and when you administer it in a gout attack important? First 10 minutes, first hour, first six hours versus, you know, waiting a day. Naomi, yeah, I mean, the earlier the better. I I want to bring uh up also you know we discuss here in the states versus golden steroids in abroad they give a lot of ACTH and and um injections I I uh in the states it's very expensive but so I think the sooner the better uh the inflammation is is greatest in the first few hours and uh and hence the pain the first few hours is when I've told patients that for every hour they delay, they're probably buying four to six more hours of pain. That's probably a decent rule of thumb or at least illustrates um the goal you have for your patients and and they tend to get it. You you would think they wouldn't need much motivation to really intercede, right?

But um Eugene Fun from Waco asked a really good question about if you are giving IL-1 inhibitors does that have effects beyond the acute gouty attack does it help the joints does it help the tophi does it help anything else other than pain you know so it depends on the half-life right so canakinumab the half-life is 28 days and hence uh it's used it's good for prophylaxis flare prophylaxis and decreases flares and anakinra it's only the half-life is only a few hours. Hence well and there's one other thing that just ought to get said and you know there there's been a good bit of study in the general medicine literature about this is that inhibiting IL-1 is cardioprotective and [clears throat] you know we we know that um based on really great data uh from the group in in England that flares are are associated with an increased risk of myocardial infarction and thrombotic disease. bad actors and so we really need to prevent flares but um if you use colchicine or if you use an IL-1 inhibitor you're not only reducing flares but you're reducing cardiovascular events so I want to ask a blanket go ahead Naomi go ahead yeah canakinumab the CANTOS trial over 10,000 patients and and we see again this long acting interleukin-1 inhibitor um and and we see decrease in those that have elevated CRP in [clears throat] in in cardiovascular events. So yeah, we know colchicine right the LoDoCo trial LoDoCo one two and and and so on and we see we know with colchicine and the story is not uh still clear but it again decreases if you had an MI it decreases your chance of an MI in the LoDoCo trials.

On a on another vein, u John Batson and Jeff Peterson have reported on a couple of series of patients treated with canakinumab in anticipation of starting pegloticase, which I'm sure we're going to get to. And uh they've essentially eliminated the risk of of post treatment flares. Well, that's interesting. Yeah, they're interesting studies.

So, we have another question about ACTH dosing. First off, I would never use ACTH. But I'm going to start by asking each of you because it's ridiculously expensive. It bankrupted the city of Rockford, Illinois when it got used after the price got increased when it was then called Acthar Gel. But long ago, before it was bought and made ridiculously expensive, did any of you use ACTH to treat gout? Just raise your hand. I don't really need an answer. Nobody. Are any of you using ACTH Acthar Gel now to treat gout? you know, um, no, but I'd like to see a really well-designed head-to-head study with an equivalent glucocorticoid dose. Maybe it is better. I mean, there's there's some biologic arguments to suggest that there may be some other effects of it, but but the right studies just haven't been done, Jack. Right. It's got an indication. It's very broad, but it was a grandfathered drug in. It was just like aspirin and colchicine. and it had all these indications that have never been truly tested and but yet they have it in their label. So there are people using it willy-nilly for all kinds of things. I'm against it obviously.

Let's move on to the next question. um what percentage of your patients are refractory or difficult to treat and I put in specifically allopurinol refractory meaning they're on al they're on now we're transitioning to urate lowering therapy and you know 0.1 is
10% 2 is 20% — most people said 20%. Between — and then a third said 10%. So that's like 75% of you said it's either 10 or 20%. 19% said a third of patients and 4% said 60%. It kind of depends on how you define refractory gout.

So I'll put in a few facts here that you guys probably know. Less than 40% of gout patients achieve a uric acid of less than six. And that's even in rheumatology. 3% of gout patients are said to have refractory disease by some definition. In clinical trials, where it's most optimal, 10 to 20% of patients do not achieve a target of six or less, and 15% have advanced tophaceous gout.

Go around the horn here and ask you what you think about these definitions. Well, first there are two issues: one is drugs that are refractory to uric acid lowering, or patients who are refractory to uric acid lowering — that is one issue. And the other issue is what percentage of patients have advanced gout.

But let me take the first part of that. I think we learned a lot from the first two phase three febuxostat trials. Both of them used as a primary endpoint the last three uric acids being less than six. And I don't remember which of the two, but one of them showed only 26% of patients achieved consistent lowering of uric acid on allopurinol 300 milligrams a day or less. So 26%. And if you looked at the very last uric acid in that six-month trial, it was 40%. That's 300 milligrams a day or less.

So refractory depends on — if you define uric acid lowering as optimizing the dose of allopurinol — the percentage of patients who are truly refractory falls significantly. We'll get into advanced gout and refractory to therapy, which is a complicated story, but I think pushing on the allopurinol or the febuxostat to get the dose up is incumbent upon the physician if they're taking care of their patients properly.

Yeah. And what's the hidden story here? I mean, I think Herb summarized it pretty darn well. I see probably 20 or 30% that you might call refractory. Half of those are situations where the doctor in the community — mostly, maybe sometimes a rheumatologist — but hasn't really pushed hard enough with urate lowering. And at least half of the remainder of that group are patients that don't want to stay on their med. The other half are people that are really difficult to treat. And that's a lot of the people that walk into our practice — that have lived out in the sticks, sometimes in urban populations where they're not getting good care. They don't have primary care. They have either neglected their gout, their doctors have neglected their gout, and they have tophi and they have serum urates in the 11 to 13 to 15 range. And they're refractory. They take a long time to get their serum urate down to target, and you can crank their allopurinol up to 600 or 800 milligrams and it's still going to take a year or more.

Yeah. I'd like to bring another problem here, and that is adherence. As you know, most patients put on allopurinol — by the end of the year they are not on allopurinol. And the other thing I've seen: primary care docs and others, when a patient has a flare, they stop their urate-lowering therapy. There are all kinds of — so education is very important, both of the patients but also the healthcare providers, to educate — because it's "just gout." It's not just gout. Dr. Sagar alluded to cardiovascular disease and many other comorbidities associated with gout. So we need to treat gout better, and I think that is part of the problem — to really educate patients, healthcare providers, their families about the severity of the disease and associated comorbidities.

I think that care involves very careful follow-up management. I think my experience with gout is that there are so many variations on a theme of how a patient may screw it up or how a doctor isn't attentive to what the patient's actually doing. I think gout patients who have really severe disease, in many instances, are much more meticulous about how they care for the disease going forward if properly educated. And the concept of gout patients not being compliant in general — I think that concept I held to, and many people do, but doing the pegloticase trials, as we moved into open-label extension, 93% of patients who were getting infused every two weeks who hadn't dropped out of the study elected to stay in the open-label trial and continue. So these patients can be actually very highly motivated, and sometimes it's us — the doctors.

And then finally, the Nottingham study done by Mike Doherty in Nottingham, England, with nurses following up the patients, showed that you can get very impressive percentages of response with uric acids less than six if you just pay attention to the patient and follow them carefully. So that's my two cents on that.

I like as a general rule — when something's not going right with any
patient to blame myself first. And you know, I think that uh of course Herb's laughing because he would blame me as well. Um because he knows me well. But but honestly, it's because uh if you look at the data, observational data, you the rheumatologist, the expert, you only achieve target, you know, 38 39% of the time. You're not you're not as great as you think you are. But there are studies that show when you're very diligent or when you look at nurse run or pharmacist run clinics, they get to they get there 80% of the time. So it's a certain amount of diligence that you the provider has to lead with um and and then the patient will fall in line through your education. I I I certainly didn't want to give the impression to anybody on this Zoom that um that we're blaming the patient. That's far from what we're thinking. The problem is is the people that we're dealing with are sick people. They have polypharmacy. They're on 20 medicines. Some weeks they can't afford some of their medicines and the allopurinol may be the one they decide not to buy. Oh, and by the way, when you start a urate lowering medicine, you may get worse. You you may flare. And patients don't always understand that. There's no other equivalent disease state where we start a drug and somebody gets worse before they get better unless we've done a really good job prophylaxing. So there's all sorts of things going on here that muddy the water in our sick patients with gout.

Yeah. I think you know I try to impress upon physicians gout is really two diseases. It's a metabolic disease and it's an arthritis. And sometimes those two diseases are at odds with one another. I used to tell patients when I'd give them their first prescription for allopurinol is no you may get worse and that doesn't mean I'm a bad doctor to sort because I get very personal about these things. Um I I think if the patient has that expectation and understands what to do with their prophylactic med should there be a flare uh the outcome's going to be better, compliance is going to be better and uh the patient's going to be happier.

Yeah. So yeah, I agree with uh Dr. Baraf. So gout is an autoinflammatory disease and a metabolic disease and only 10% of patients are on anti-inflammatory prophylaxis in real life. So really when you give urate-lowering therapy the patient should be started on anti-inflammatory prophylaxis whether it be colchicine which is the only approved drug um for anti-inflammatory prophylaxis or you choose another but um anti-inflammatory prophylaxis is is not commonly used.

Agreed. Okay let's move on. Um our next is what defines refractory gout or difficult to treat gout and I really, you know, there is no formal definition here. Um, and but I'd be interested in what our experts think. When we ask the audience, you could see they're a little all over the map. Failure to achieve target 42%, recurrent uh flares, polyarticular flares in 32% and 22% see uh tophaceous destructive gout as being, you know, part of that worst case scenario that we really don't want to manage. Comorbidities are a big contributor to this, but most people feel that's not the main driver in this subset of people, which again is probably somewhere between 3 and 20%. Um, when you look overall, Naomi, how would you define — I'm going to ask you to speak loudly because we us men here are speaking much more loudly than you and I want you to be heard as much as them. Naomi, what do you think is your definition?

Sorry, I didn't — difficult. Forgive me. So, we actually now have this definition of severe gout and we define it as two or more flares in the last year. And then we talk about gout and failure to reach the target is part of that. But severe tophaceous gout with many flares. But how can that be severe when that's the age-old rule since 1960 that two or more flares merits treatment with urate lowering therapy? You know, there's a question about this refractory gout. Uh who's responsible for that? Are we giving enough medicines? Is this really refractory? And that's why the the term of severe gout came into play.

I see. Yeah. Um and you know uh since uh difficult to treat RA, D2T you know PsA and AS got into this and um they had patient groups on the advisory committees and the patients didn't want to be called difficult you know like um they were offended. I mean I'm kind of honored when someone calls me difficult but they not so much. So severe um uh you know or or refractory those are probably better terms. Um Ken, how how would you address this?

Well, Jack, I think we've covered it pretty well in in saying that we're really not — we don't have a good way to define it. It's multifactorial. And I think we to be really candid, we have to agree that some of this has come from our colleagues, well-meaning colleagues who are developing drugs, right? And so we we have a market now for people that have refractory gout. These are people that are difficult to treat.
Some because they're doctors aren't doing the right thing. Some because the patients aren't getting enough of the medicine despite the doctors trying. And some because their disease — or they're just producing too much. Their kidneys are not getting rid of it well enough. They've got such a huge body burden that it's going to take years and years with conventional urate-lowering therapy to get to target. These are the reasons, and you can pick your group, your subgroup, but they're all the people that we have to do better with. And you know we don't have a lot of drugs. We don't have a lot of drugs compared to rheumatoid arthritis, even lupus. We've got just a few. We need more.

Before you start, I want to point out — as someone who's been involved in all the trials — that new drugs coming up in the future, new uricase drugs, new IL-1 inhibitors, we talked about the inflammasome, NLRP3 and whatnot. Honestly, those probably are going to more likely be used in people who are refractory and difficult. But if you look at the biologics that are approved, they have very pedestrian indications, right? None of them say only people who failed everything can get this drug.

So, Jack, I think it's a little bit like pornography. You know it when you see it.

To add to Ken's point, some patients just have never had treatment, or have been to the emergency room twice in 10 years and have let the disease wash over them. And the way the indications for pegloticase are written in the package insert are a little ridiculous. If you try to diagram the sentence for whom these drugs are indicated — patients for whom an optimal dose of uric acid-lowering xanthine oxidase inhibitors fail to control the signs or symptoms of gout or control of the serum uric acid — it's all over the place. It provides the ability for an insurance company to deny coverage, but it doesn't provide a lot of light or understanding.

But if you see a patient who can't count change, button to button, grip silverware — a patient who's oozing urate from their fingers or from their toes, who have ulcerations around the ankles from erupting tophi — those are clearly patients with gout in need of very aggressive therapy. And I think that's what you're driving at with this question. What defines difficult-to-treat or refractory gout? The answer to this question, as far as I'm concerned, is all of the above, or any of the above. Because these are the kinds of problems that we deal with. I think that when you get really aggressive with treatment, it needs to be a patient who is functionally impaired, for whom a more rapid and timely approach to getting them better should be implemented.

Okay, I think that's fair. Can I just talk about — forgive me — the comorbidities? I love it, because we're now talking about precision medicine, really, and treatment of gout with comorbidities. And I think that's the wave of the future. It's not going to be just gout; it's going to be gout and associated comorbidities, and the causes of those are intertwined with those for gout.

I love the last answer, actually, because I think that's the futuristic precision treatment. So, to that point, precision-wise, if we're talking about a diabetic who presents with gout and recurrent flares, the use of an SGLT2 inhibitor plus allopurinol or febuxostat would be better than one or the other alone. But that doesn't necessarily mean the patient's functionally impaired. It means that it's going to inform what therapies you bring to bear on that patient. If they're functionally impaired in a more persistent way, that's a kind of different definition for refractory. And almost all of those patients have multiple comorbidities.

So, the audience — when they were asked questions leading up to this question on the right, which I want to address first — they were asked questions about difficult-to-treat and refractory gout, and I asked them which new or novel therapy are you most likely to use when treating gout? I'm asking them: what are you looking forward to? What's going to be your next expansion? Pegloticase was 45%. Canakinumab was 23%. SGLT2, as you mentioned, was also 23%, and about 10% GLP-1s.

This is interesting — yes, there are not enough people using pegloticase, although rheumatologist surveys we did before — maybe I'm going to show you that next — basically said that they have great hope for pegloticase but also admit to not using much of it. Maybe this will change with more uricase-targeted therapy being made available.

What do you think, Naomi, as far as where the market's going to go here and what rheumatologists will use? Yeah, so I
think you know the SGLT2 inhibition is interesting. So urate lowering is not as much lower than that with conventional urate lowering therapy. Um, one interesting thing is as the urate lowering therapy, you really don't see initial flares. So, that's a benefit, but they're anti-inflammatory. And I think, you know, we're seeing reduced flares when using SGLT2 inhibitors. There's an ongoing NIH funded study now looking at that. We're going to actually have the randomized control trial and the results because what we have is from mostly diabetics and showing that SGLT2 inhibitors reduce flares.

The GLP-1 story is also interesting, combating both really diabetes and obesity, and I think the story is again anti-inflammatory because again serum urate lowering — we don't have any studies as of yet in gout but they're both good anti-inflammatory drugs. And I think prophylaxis, anti-inflammatory prophylaxis really in our gout patients — I think that is what we're going to see. Canakinumab is coming out of patent. Um, I don't know that we're going to see much. Um, hopefully we're going to see other drugs and there's a Chinese IL-1 one now that's been published to have completed phase three. I don't know that they're coming to the states though, and it is a very good medicine, changed really the prognosis of severe gout, but it's too expensive.

And Herb, are you surprised that the data thus far on these new diabetes drugs — they both work in diabetes and they cause weight loss — the GLP-1s are better at weight loss than SGLT2 inhibitors, but the SGLT2 inhibitors are far better at gout than the GLP-1s. Do you have an understanding of that?

You know, in preparation for tonight, I looked at a couple of studies and I saw a meta-analysis of 51 studies looking at SGLT2 inhibitors and they pretty much show about a one and a half point drop in serum uric acid level independent of the use of a xanthine oxidase inhibitor. So, it's additive to the xanthine oxidase inhibitor and probably plays a role. GLP-1 agonists actually increase the risk in the first year of treatment of gout flares, probably because patients may be ketotic or the breaking down of protein leads to more acidic urine and competition for urate excretion, but I would think that over time gout would be better controlled in association with the weight loss that's achieved with those drugs.

Um, yeah, frankly in many patients I think pegloticase is overused. I think it's a very serious decision to start a patient on a uricase. I don't think the presence of a golf ball on each olecranon process is an adequate reason to start pegloticase. I think the patient needs to be functionally impaired, and then remember that when it's over they need to be back. It's just a bridge treatment. They need to be back on uric acid lowering therapy. So, it's not an endgame. It's a transition game with a uricase, with pegloticase or other uricases that may be coming down the pike. I hope that answers your question.

Yeah, Ken, hold on a second because I want to challenge Herb on this a little bit in that functional impairment I agree with, but there's this psychologic impairment of having those ugly tophi and whatnot. So when — and you've done the trials, you got way more experience than I do with pegloticase. What do people marvel at most? Their functional improvement or that the nodules are dissolving?

You know, a patient will — you walk in the room on the third or fourth visit and the patient will say, "Look at this. I can use my hands." They're fascinated by it. Um, but so I think function is a really big — you know, obviously pain, but function is a really big part of this. You can get patients' gout pain under control, most patients, even those with chronic synovitis. And like as I suggested, I think you develop a sense of who needs this drug, but it isn't just — let me take the golf ball out and just make it — it's not a marble here and here. It should be playing a role in the patient's life and in their psyche, or both. Okay, before you commit them to this treatment, because even with giving patients immunosuppressants to decrease the risk of infusion reactions and increase the likelihood of improvement, the patient is subjecting themselves to significant risks, and I think the punishment needs to fit the crime.

Okay. Ken, you wanted to comment on this?

No, I think I'm on board with Herb's approach. We use pegloticase as induction chemotherapy for people with really severe gout that have a huge body burden, typically with sizable tophi. Um, back to the SGLT2s and the GLP-1s — SGLT2s have a direct uricosuric effect. They have a mechanistic way to reduce urate. Um, however, they're not well
tolerated. Patients don't like taking them because they have polyuria and they develop candida. So, they're not popular. GLP-1s obviously are endemic in use. And as was suggested that over time weight loss will benefit gout, but becoming ketotic or eating more protein in your diet is likely to lead to some transient effects. And the meta-analyses don't show significant benefit yet of those drugs on urate, but maybe over time with more potent ones they will.

Yeah. The other question was what's your preferred drug in an allopurinol refractory patient? They're switching to another urate lowering therapy. That seems reasonable, but I also challenged them. You know, 20% said they'll go to pegloticase. Combination ULT — does anybody use combination ULT or is that a special kind of stupid? Is that what you mean? A uricosuric and a xanthine oxidase inhibitor. Is that what you — I left it up to the imagination. That would be the simplest and legally right answer, that you could use a ULT with probenecid under the right conditions, but you know, using febuxostat and allopurinol together — are you asking for trouble? I don't know anybody that does that.

I don't think you're asking for trouble. I remember I had a patient — for me it's been very rare that I haven't been able to lower uric acid below six, extremely rare. I can think of two or three patients over the last 20 years where I couldn't do it, and on one of these occasions I called Richard Johnson, who was at the time a nephrologist at University of Colorado, who's a brilliant guy. He said, "Why don't you try febuxostat and allopurinol together?" I said, "Really?" He said, "Well, you know, they have a slightly different mechanism of action." I said, "Really?" So I tried them together. It did nothing. But that's rather anecdotal and I don't see a role for doing that. You know, in treating hypertension we do that all the time, but using drugs with two distinctly different mechanisms — I think that makes a lot of sense in gout.

Sure. And Richard Johnson's got a great article about gout and the kidney on RheumNow that people should read.

Let's move on to the next question. Who's the ideal candidate for pegloticase? We talked about this and I don't have function as an answer, but non-resolving tophi was the lead answer in half the people, failing to achieve target or greater than two attacks. But anybody have a different view here?

And then here — which treatment do you use to dissolve, or I'm sorry, to resolve or to treat tophi? And you can see — oop, sorry about that — that a fair number — I got to — oh my goodness, I'm trying to move my pointer so I can see — allopurinol, 25% were using allopurinol, but a uricase agent in 28%. So despite the fact that 28% of rheumatologists are not using pegloticase based on surveys and usage data — does any of this surprise you about the need or the use of pegloticase as the only available uricase drug?

You know, let me chime in here because I was involved in the first phase 2 trial and we had a patient with before and after photographs 12 weeks apart. We showed — a physician showed his toe disappearing, and he had a dozen pairs of shoes he couldn't wear and he was able to wear them, and a year later holes in his bone had actually healed — you saw new bone formation. And I wrote it up with one of my partners, Alan Matsumoto, and somebody at Savient, the company that was developing the drug. And I didn't think you were going to need to use this drug all that long for debulking patients with tophi, but I forgot what question I was answering, so I'll stop here unless you remind me. [laughter]

All right, we're going to move on. I think — can I add something, please?

You know, we talk about different medicines. Allopurinol, for instance — and I've learned from a colleague who had gout and Zyloprim worked for him, but other allopurinol brands did not. So this is also important when we talk about using allopurinol. Just so you know, different brands can work better, and I've found Zyloprim to be more efficacious in some of these patients. It's certainly worth a try and would probably be backed by insurance companies at that stage.

Which immunosuppressant should be considered to maximize pegloticase responses? The overwhelming answer from John Botson and Dr. Peterson is methotrexate. But before that, I remember having conversations with Ken about whether mycophenolate or azathioprine. So Ken, what happened to our great ideas about mycophenolate and azathioprine?

Well, we did a study — actually a pilot study — looking at mycophenolate in combination with pegloticase, and guess what, it was significantly better than pegloticase alone in achieving targets. So the pilot study worked. Mycophenolate is an option, and for
people that have severe liver disease, severe kidney disease where there's a contraindication to using methotrexate, mycophenolate is an option to consider. The first paper to appear in the literature regarding the use of an immunosuppressant was written by Ai Bhanu and Mike Pillinger and Rob Keenan, looking at azathioprine, and I reviewed the paper and I thought — for publication — I thought the story was a little screwy but the concept was extremely important. And then I was involved with a clinical trial with Peter Lipsky and we looked at azathioprine and it was a positive — it was a small study but the results were positive, it had an impact. So I think the answer — and leflunomide has been reported to be effective — so the answer is all or any of the above would be sufficient when there's a contraindication to the others. And you're probably driven by contraindications. I mean, if you can't be on allopurinol, that's a no-no that we want to remind people of.

And I'll remind people that the very first time I came into this clinical situation was in the development of a drug called CA2 by Tiny Maini and Marc Feldman, also known as infliximab. The original articles published in Lancet talked about anti-drug antibodies, and the drugs that they used to suppress anti-drug antibodies were not methotrexate but sulfasalazine. The idea is you have to have a drug that will affect B cells, and it's all pretty much fall under the heading of DMARD. And I do believe that methotrexate is a part of the indication for pegloticase and that's probably why you want to use that or consider that, but as was said, other DMARDs will work here as well. So why not.

Okay, what about URAT inhibitors — which one of you is working on URAT inhibitors right now in drug development? Well, we're doing some studies. There's several. It's really a race to the finish line. There's probably close to a dozen agents that are in various stages of development. Two are in late phase three. That's posited and doinered. The Tinerad is actually in use in several countries in Asia. They both look a little more like benzbromarone than anything else. And the preliminary data looks pretty good in terms of their efficacy. And we're waiting for phase three to confirm that and to look further at any safety signals. So these drugs work by blocking urate reabsorption. That was the MOA for lesinurad that went on the market and off the market. Who wants to tell that story? What's different?

Yeah. So what's different is pharmacokinetics to some degree, sort of onset, offset, binding — different properties of how you interact with URAT1, how long it's on. You know, is there a burst of urate into the kidney? I think there's a good likelihood that at high enough doses any of these drugs are going to have some renal toxicity. I don't think that's going to be very unlikely, but trying to find the right dose and particularly thinking about slow titration, possible combinations — there's going to be ways with these more potent agents to use them hopefully more safely and to see some real benefits, but we'll find out.

I think there are a couple of questions about these, but the ultimate question is when it gets to the marketplace, will physicians use two therapies together? Will they use a uricosuric? Again, I think Ken, you're right about risks — that there will be risks to the kidney. Lesinurad ostensibly came off the market because of a few rare cases of hepatotoxicity and because 10 to 15% of patients on higher dose alone developed a rise in the serum creatinine. But I don't think that that was why my colleagues didn't use lesinurad. I think it was lack of interest, lack of aggressiveness about treating uric acid — lowering uric acid. And I just wonder how the marketplace is going to receive these drugs when they come out.

Herb, don't you think some of that was because the ability of lesinurad to actually be effective at lowering uric acid and, you know, better managing gout wasn't all that great until you combined it with allopurinol? Well, it was better with allopurinol, but the numbers alone weren't bad. I mean, you got uric acids below five in a reasonable percentage of patients, although you had to use the higher doses which may have been nephrotoxic. But I think the real problem is whether physicians are going to accept these drugs into their armamentarium and use them.

Okay, folks. We got two minutes left. I'm putting up a slide from a current publication. It basically says that we're either — you know — doing urate lowering, we're going after inflammation, we're going after the kidney with URAT1s. Anybody want to talk about where gout is going in drug development? Anything that's new that we haven't yet? So I think there's a
couple things we didn't talk about. One is the new NASP, which looks exciting based on its data. It looks, you know, equivalent to PEGylase without immunomodulatory therapy, and we need more uricase cases. We'd be interested to know whether we could give that to people that have failed pegloticase. That would be a population of great interest.

The other thing that's happening is we're getting a lot more creative in how we're going to deliver drugs. We could use mRNA, for example, to possibly endogenously produce uricase. That could be really exciting to have the liver generate it. And so there's different strategies that are very preliminary, but could be very exciting.

Naomi, where are you excited? Yeah, I'm excited about combination of urate-lowering therapy such as the uricases. There's also the Protalix uricase — plant-based — that's now in phase two, and anti-inflammatory agents. You see here quite a few in the pipeline, and LRPF inhibition — very important in gout and associated comorbidities.

Yeah, I think for this really severe patient who needs pegloticase but has had a reaction to it, there is reason to believe that SEL-212, also called NASP, may be a good alternative. The antibodies that form against pegloticase are against the polyethylene glycol and uricase in combination, whereas the antibodies that form against NASP are against uricase alone — they do not involve or need the PEG to neutralize the enzyme. So it may be an alternative for patients who can't handle pegloticase, and instead of every two weeks it's every four weeks, and the results are similar — perhaps not quite as good, but certainly comparable. So it's an option for the patient who's got extreme disease and has no other options for treatment.

Yeah. And importantly, the older the patient, the more responsive they are to a uricase — over the age of 50. That's interesting.

And again, in NASP they have — one of the moieties is sirolimus, which is a calcineurin inhibitor playing the role of methotrexate in making sure that you don't get the anti-drug antibodies and whatnot.

Anyway, fabulous folks — I want to thank all of you for enlightening us tonight with a lot of new information that's going to be important going forward in managing gout. I want to encourage the audience to look at any one of these Tuesday night rheumatology sessions. They're one-hour recordings, one-hour videos. You can check it out on a podcast while you're driving. They were all really wonderful. There are other things that are up on the website that you may not have seen, including cases on gout called QD Clinics and a series of videos that have to do with gout as a systemic disease. We have Dr. Fischler doing a video on mortality and gout that just got posted yesterday. It's a really fabulous video. Again, thanks folks. Hope you have a good evening. We'll talk soon.