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 with 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 gonna talk about tonight. I'm going to begin by asking them to introduce themselves. Let's start with Naomi.

Hi everyone. Good evening. I'm Naomi Schlossinger, a Galtologist trained with the number one gout expert Doctor. Schumacher as a fellow and have been in the field for many years.

Excellent. Herb?

Herb Barreff. I 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. And I'm

delighted. We won't go into why you signed up for that, Doctor. Barack, but it's interesting nonetheless.

You get these little bottles.

And Ken.

Hi, Ken Thagg, Director Director of Clinical Immunology and Rheumatology at the University of Alabama at Birmingham. Interestingly, Erb, it was actually Eugene Ball at University of Alabama at Birmingham that described Saturnine Gout and Moonshine many, many years ago. We see some really bad gout down here in the South.

That's wonderful.

Gene visited, we commiserated.

Let's go to slides that we'll use our template for this evening. Here we go. Boom right there. I'm going to go to full screen. I want to first recognize that this month on gout and education on gout has been rich in content.

And we want to thank, the support of Sobe, throughout the month in making sure that we bring you only the best in written content, videos, podcasts. It's really been an incredibly rich week. We want to thank you the audience for 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. By clicking on the Q and A box, we'll see your question and we'll address it in this session.

I think that's it for the housekeeping. Get a glass of wine, a cup of coffee. You know that what we do prior to these Tuesday night rheumatology sessions as 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. We wanna thank two seventy four of you who answered this survey with little or no notice. Note that again, 39 countries, two thirds are from The United States, 93% were rheumatologists and two or 3% were fellows or advanced practice providers.

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. 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 two thousand and eight, twenty sixteen and just recently. But anyway, when you look at gout and its development, we have these early eras which was really focused on gout flares and what drugs you use. Back then it was urate lowering therapy, but are you an over producer or under excreter?

And then in two thousand, twenty ten, it was treat to target and the development of new drugs, including not just for buxastat, but our first biologic, which was peglodecase and then others, and then the imaging became the big issue. And really like in the last ten years, it has been about advanced therapy and biologics and drug development. That's what we're going to discuss tonight with these folks who are involved in the clinical trials and involved in how these drugs will be used. Let's begin with the first question to our almost 300 rheumatologists and I asked them which biologic is FDA approved for gout? There were actually two right answers here.

That's sort of a no no in the rules, but I can break the rules since I sent it out. The right answers here are peglodecase and canakinumab. 51% said peglodecase, and you can only answer choose one on these survey questions. And 22% said canakinumab, but 20% believe that anakinra is maybe it should be, but it is not. And tocilizumab is a pipe dream and maybe we can talk about whether that belongs on the list for the future.

But the right answers here was cristexa peglodecase being approved in September 2010, with the indication of being that it is to be indicated for chronic gout, 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. Then I'll add to Canakinumab. Someone's got to mute themselves. Canakinumab was approved in August 23. Here the indication was in patients who could not take colchicine or nonsteroidals either because of intolerance or other reasons.

And 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. There.

Yeah, so I think the anakinra data, Jack, or the anakinra response is curious. And 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-one inhibition in general?

Yeah, so I guess I will tell you why can I get an approval because we actually finished conducting the studies and I presented this in the ACR in 2011, 2010, 2012 and it wasn't approved by the FDA? So Doctor. 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 rilanoseptin canakinumab, but neither is approved for prophylaxis and canakinumab as Ken alluded to was approved compared to the forty milligrams of Trimecilin I'm which is, in the European countries, that is the dose given for acute flares. Hence is why we chose that dose as a comparator.

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

Well, I was involved with the Rolanoscept 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 backwards and upside down. Canakinumab is exceptionally expensive. And anakinra, if you buy a week's worth and you give a patient one hundred milligrams daily for three days and put the rest in the fridge, the patient probably can treat two more flares after the first one should they have another refractory flare.

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, canakinoreb's 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 canakinamab you're talking about there.

Canakinamab, yeah.

To any of you, when you use an anakinra in acute gout, do you use that in addition to a non steroidal or culture seat at the same time or in place of?

I mean, you have to, usually it's in place of, it's usually in somebody that has a contraindication or has failed the other stuff. Sometimes we use combo of things in people that are really rip roaring And that would be one way to do it certainly. It's not totally innocuous. There are infectious risks. I think we feel like IL-one 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.

Although in kenakinumab for instance, there's data of over ten thousand patients and really there are no serious infection as opposed to TNF inhibitors. Yeah, I'd like to add though that for acute flares, remember that patients have kidney disease and they may have liver disease and I don't use so much Golgi seed 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 six to twelve 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 GREED trial,

their

primary endpoint was fifty percent reduction at twenty four hours, only thirty seven percent. Get to that, so almost seventy percent.

Yeah, well, but the trial didn't allow initiate. You call had into a call center and the treatment had to start within twelve hours of the onset of the flare, which is-

All right, you guys are talking about a trial that we know nothing about. The

Yeah, 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 based on that work. The good news is that 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. It was in a randomized controlled trial. It's actually very interesting as Doctor. Saag alluded to.

Let's go on to our next question. Here we're going to say, what is the indication for IL-one 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-one inhibitor FDA approved. The lead answer was if NSAIDs or colchicine is contraindicated, that's forty percent. Acute gout flares, that's right at twenty nine percent.

So those two, that's sixty nine, almost seventy percent people got it right. Only severe gout flares, that's not in the language. Doesn't have to be particularly severe or horrific. 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. 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-one inhibitor other than gout flares, can't use the other drugs, the other drugs don't work.

Jack, it gets to the issue of what Herb raised earlier. I mean, drugs work well, but they've got to be given parenterally, which patients don't really like that much. They're very expensive. Anakinra is off label, so you got to hassle with the insurance company to get it. There's a lot of investigation now looking at oral inhibitors of IL-one and NLRP3 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. These occur in the middle of the night on the weekends. It's just 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. You've No,

I think Herb, that is exactly the strategy that's needed. In fact, you could imagine where you could give somebody a lockbox 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, that trial and the company was roundly condemned because of the price they placed on Colchrys. It was about 50 times more than colchicine prior to its approval, just 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. Luis Torre Grosso. Hey, Luis, I saw you last week at the Florida Society of Rheumatology meeting. I asked, what percentage of gout flares are refractory to standard therapy, colchicine and nonsteroidals?

So that you would consider an IL-one. Does anybody have a number there?

I can't give you a number, I wish I could. I will tell you that you take some of these people that have chronic gout, it's a chronic arthritis, they have flares constantly, they have tophi, they're ulcerated, they're in the hospital infected, they're flaring, we're not sure if they're septic or if they've got gout. These are some of the people we're dealing with and it's just a real mess. So yes, we try what we can to try to settle them down and it often does pull in an IL-one inhibitor 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.

The timing of therapy and when you administer it in a gout attack important first ten minutes, first hour, first six hours versus waiting a day, Naomi?

Yeah, I mean, the earlier the better. Wanna bring up also, we discuss here in The States, NSAIDs, Cush, Cush, Cush, steroids. Abroad, they give a lot of ACTH injections. The States, it's very expensive. So I think the sooner the better.

The inflammation is greatest in the first few hours 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, the goal you have for your patients and they tend to get it.

You would think they wouldn't need much motivation to really intercede, right? But, Eugene Fung from Waco asked a really good question about if you are giving IL-one 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?

So it depends on the half life, right? So canakinumab, the half life is twenty eight days and hence it's good for prophylaxis, flare prophylaxis and decreases flares. And the kinrad, half life is only a few hours.

And there's one other thing that just ought to get said and there's been a good bit of study in the general medicine literature about this is that inhibiting IL-one is cardio protective. And we know that based on really great data from the group in England, that flares are associated with an increased risk of myocardial infarction and thromboembolic disease, bad actors. So we really need to prevent flares, but if you use colchicine or if you use an IL-one 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, kanekinumab, the CANTOS trials over ten thousand patients and we see again this long acting interleukin-one inhibitor and we see decrease in those that have elevated CRP in cardiovascular events. So yeah, we know colchicine, The Lodoco trial look one, two and so on and we see, we know what colchicine and the story is not still clear, it again decreases if you had an MI, it decreases your chance of an MI in the MODOCA trials.

On another vein, John Botson and Jeff Peterson have reported on a couple of series of patients treated with canakinumab in anticipation of starting peglodecase, which I'm sure we're gonna get to. And they've essentially eliminated the risk of post treatment flares.

Well, that's

interesting. Yeah, they're interesting studies.

So we have another question about ACTH and 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, Actar Gel now to treat gout?

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, some biologic arguments to suggest that there may be some other effects of it, the right studies just haven't been done, Jack.

Right, it's got an indication, it's very broad, but it was a grandfather drug in. It was just like aspirin and colchicine, it had all these indications that have never been truly tested, But yet they have it in their label. 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.

What percentage of your patients are refractory or difficult to treat? And I put in specifically allopurinol refractory, meaning they're on now we're transitioning to urate lowering therapy. And zero point one is ten percent, zero point two is twenty percent. Most people said twenty percent between and then a third said ten percent. So that's like seventy five percent of you said it's either ten or twenty percent.

Nineteen percent said a third of patients and four percent said sixty percent. It kind of depends on how you define refractory gout. So I'll put in a few facts here that you guys probably wrote. Forty percent of gout patients less than forty percent achieve a uric acid of less than six. And that's even in rheumatology.

Three percent of gout patients are said to have refractory disease by some definition. In clinical trials where it's most optimal, ten to twenty percent of patients do not achieve target of six or less, and fifteen percent have advanced tophaceous gout.

Me jump

around the horn here and ask you what you think about these definitions.

Jack, well, there are two issues. One is refractory uric acid, drugs that are refractory uric acid lowering, or patients who are refractory to uric acid lowering 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 twenty six percent of patients achieved consistent lowering of uric acid on allopurinol three hundred milligrams a day or less. So twenty six percent, and if you looked at the very last uric acid in that six month trial, it was forty percent. That's three hundred 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 dofacia scout and refractory to therapy, which is a complicated story. But I think pushing on the allopurinol or the febuxostat to get the dose down is incumbent upon the physician if they're taking care of their patients properly.

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 your rate lowering. At least half of the remainder of that group are patients that don't wanna 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 in in our practice, that live out in 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 TOFI. 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 six or eight hundred milligrams and it's still gonna 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 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 going therapy or that there are all kinds of so education is very important both of the patients but also the healthcare providers and to educate because it's just gout, it's not just gout. Doctor. Saag 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 and 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 in 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 peglodecase trials, as we moved into open label extension, ninety three percent 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 Dougherty 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. I think that, of course, Herb's laughing because he would blame me as well because he knows me well. But honestly, it's because if you look at the observational data, you the rheumatologist, the expert, you only achieve target thirty eight percent, thirty nine percent of the time. 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 there 80% of the time.

It's a certain amount of diligence that you the provider has to lead with and then the patient will fall in line throughout your education. I

certainly don't want to give the impression to anybody on this Zoom we're blaming the patient. That's far from what we're thinking. The problem 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 may flare and patients don't always understand that there's no other equivalent disease state where we start a drug to make 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. 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, because I get very personal about these things.

I think if the patient has that expectation and understands what to do with their prophylactic meds, should there be a flare, the outcome's going to be better, compliance is going to be better, and the patient's going to be happier.

Yeah, I agree with Doctor. Barav. So, GAD is an auto inflammatory disease and a metabolic disease, and only ten percent of patients are on anti inflammatory prophylaxis in real life. So really when you give urine like therapy, patients should be started on anti inflammatory prophylaxis, whether it be colchicine, which is the only approved drug for anti inflammatory prophylaxis or you choose another, but anti inflammatory prophylaxis is not commonly used.

Agreed. Okay, let's move on. Our next is what defines refractory gout or difficult to treat gout? And I really, there is no formal definition here. I'd be interested in what our experts think when we asked the audience, you could see they're a little all over the map, failure to achieve target forty two percent, recurrent flares or polyarticular flares in thirty two percent and twenty two percent see tophaceous destructive gout as being 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 three and twenty percent. When you look overall, Namely, how would you define refractory gout? I'm gonna 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 So of difficult to read

we actually now have this definition of severe gout and we define it as two or more flares in last year. And then we talk about the facial scan and failure to reach the target as part of that, but severe to facials gout with many flares.

But how can that be severe when that's the age old rule since 1960 that two more flares merits treatment with your rate lowering therapy?

There's a question about this refractory gout. Who's responsible for that? Are we giving enough medicines? Is this really refractory? And that's why the term of severe gout came into play.

I see. Since Yeah. Difficult to treat RA, D2T RA, PSA and AS got into this and they had patient groups on the advisory committees and the patients didn't wanna be called difficult. Like they were offended. I mean, I'm kind of honored when someone calls me difficult, but they not so much.

So severe or refractory, those are probably better terms. Ken, how would you address this?

Well, Jack, I think we've covered it pretty well in saying that we don't have a good way to define it. It's multifactorial. I think to be really candid, we have to agree that some of this is come from our colleagues, well meaning colleagues who are developing drugs. And so we have a market now for people that have refractory gout. These are people that are difficult to treat, some because their 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 gonna 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 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 trials that new drugs coming up in the future, new uricase drugs, new URAP1 inhibitors, we talked about 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, have very pedestrian indications. None of them say only in 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. So, to add to Ken's point, some patients just have never had treatment or have been to the emergency room twice in ten years and have let the disease wash over them. And so the rules and the you know, the way the indications for peglodecase 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, xanthine oxidase inhibitors fail to control the signs or symptoms of gout or control the serum uric acid. It's all over the place, provides the ability for an insurance company to deny coverage, but it doesn't provide a lot of light to 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 that's what you're driving at. 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, 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. Guess there's Can

I just talk about forgive me, the last, the comorbidities, where 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 gonna be just gout. It's gonna be gout and associated comorbidities and the causes of those are intertwined with those for gout. So 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 SGL-two 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, it's a totally in a more persistent way, that's a kind of a different definition for refractory. And all those patients have multiple comorbidities or almost all of them do.

So the audience when they were asked questions that we were leading up to this question on the right, want to address first. They were asked questions about difficult to treat and were somewhat refractory. And I asked them which newer 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?

Peglodecase was 45%, Canakinumab was 23%, SGLT2 as you mentioned, was it also 23% and about 10% GLP ones. So this is interesting. You know, yes, there are not enough people using Peglodecase. Although rheumatologists surveys we did before maybe I'm going show you that next, basically said that they have great hope for pegvodecase, but they also admit to not using much of it. Maybe this will change.

Maybe this will change with more uricase targeted therapy being made available. What do you think Naomi, as far as where the market's gonna go here and what rheumatologists will use?

Yeah, so I think the SGLT2 inhibition is interesting. So urate lowering is not as much lower than that with conventional urine lung therapy. One interesting thing is as opposed to urine lung therapy, we really don't see initially 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, so we're gonna actually have the randomized controlled trial and the results because what we have is from mostly diabetics and showing that SGLT2 inhibitors reduce flares.

The GLP-one story is also interesting combating both really diabetes and obesity and I think the story is again anti inflammatory because again serum urate, lorraine, we don't have any studies as of yet in gout but they're both good anti inflammatory drugs. I think prophylaxis, anti inflammatory prophylaxis really in our gout patients, I think that is what we're gonna see. Canekinumab is coming out of patent. I don't know that we're gonna see much. Hopefully we're gonna see other drugs and there's a Chinese interleukin-one beta that's been published to have completed phase three.

I don't know that they're coming to The States though. And Toboticase is a very good medicine changed really the prognosis of severe gout, but it's too expensive.

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

In preparation for tonight, looked at a couple of studies and I saw a meta analysis of 51 studies looking at SGL2, T2 inhibitors. And they pretty much show about a one and a half point drop in serum uric acid level independent of the use of xanthine oxidase inhibitor. So it's additive to the xanthine oxidase inhibitor and probably plays a role. GLP-one 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.

Frankly, in many patients, think pegylotocase 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 peglodecase. 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 end game. It's a transition game with a uricase, with peglodecase or other uricases that may be coming down the pike. I hope that answers your question.

Ken, on a second. I wanna challenge Herb on this a little bit in that functional impairment I agree with, but there's the psychologic impairment having those ugly tophi and whatnot. And you've done the trials, got more experience way more than I do with peglodecase. What do people marvel at most that their functional improvement or that the nodules are dissolving?

You it's a patient, when 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. So I think function is a really big, 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 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, 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.

Ken, you wanted to comment on this?

No, I think I'm on board with Herb's approach. We use pegilotic cases induction chemotherapy for people with really severe gout that have a huge body burden, typically with sizable tophi. Back to the SGLT2s and the GLP-1s, SGLT2s have a direct uricosuric effect. They have a mechanistic way to reduce urate. 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. 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 challenge them, twenty percent said they'll go to pegvodecase, combination ULT. Does anybody use combination ULT or is that a special kind of stupid?

Is that what you mean a uricosuric azathine oxidase inhibitors? Is that what you mean?

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 using febuxostat and allopurin altogether, 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 that I See, 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 twenty years where I couldn't do it. And on one of these occasions, called Richard Johnson, who was at the time a nephrologist at University of Colorado, who's a brilliant guy, said, why don't you try febuxostat and allopurin altogether? I said, really?

He said, well, you know, they have a slightly different mechanism of action. I said, really? So I tried them together. I did nothing. But that's rather anecdotal.

And, I don't see a role of doing that. Okay. In treating hypertension, we do that all the time. But using drugs with two distinctly different mechanisms, think that makes a lot of sense in gout.

Sure. And Richard Johnson's got a great article about the gout and kidney on RheumNow that people should read. Let's move on to the next question. Who's the ideal candidate for pegilodecase? We've talked about this and I don't have function as an answer, but non resolving Tollfi was the lead answer and half the people failing to achieve target or greater than two attacks.

But anybody have a different view here? What's that? And then here, weeks past, which treatment do you use to resolve or to treat ToFi? You can see, oops, sorry about that. A fair number that was oh my God, I'm trying to move my pointer.

Can see allopurinol of twenty five percent. We're using allopurinol but uricase agent in twenty eight percent. So despite the fact that only twenty eight percent of rheumatologists are not using peglodecase based on surveys and usage data. But does any of this surprise you about the need or the use of peglodecase as the only available uricase drug?

Let me chime in here because I was involved in the first phase two trial and we had a patient with before and after photographs at twelve weeks apart. We showed, it's a physician, showed his tophi disappearing, and he had a dozen pair of shoes he couldn't wear, and he was able to wear them. And a year later, holes in his bone had actually healed. We saw a 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 gonna need to use this drug all that long for debulking patients with TOFI, but I forgot what question I was answering. So I'll stop here unless you remind me.

All right, we're gonna move on. Think we're gonna 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 Xyloprim 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 for, and I've found Xyloprim to be more efficacious in some of these patients.

It's certainly worth a try and would be probably backed by insurance companies at that stage. Which immunosuppressant should be considered to maximize pegilodecase responses? The overwhelming answer from John Boston and Doctor. Peterson is methotrexate. But before that, I remember having conversations with Ken about whether mycophenolate or azathioprine.

Ken, what happened to our great ideas about mycophenolate and azathioprine?

Well, we did a study and it actually was a pilot study looking at mycophenolate in combination with peglodecase. And guess what? It was significantly better than peglodecase alone in achieving targets. 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 rexate, mycophenolate is an option to consider.

The first paper to appear, in the literature regarding the use of immunosuppressant was written by, Adi Bruhanu 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. 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 if there's a contraindication to the others.

Right, and you're probably driven by contraindications, right? I mean, if you can't be on allopurinol as a Thioprine, that's a no no that we wanna remind people of. And I'll remind people of the very first time I came into this clinical situation was in the development of a drug called CA2 by Tiny Mani and Mark Feldman, also known as infliximab. The original articles published in Lancet talked about anti drug antibodies and the drugs that they use to suppress anti drug antibodies or not methotrexate but sulfasalazine. The idea is, have to have a drug that will affect B cells and they all pretty much fall under the heading of DMARD.

I do believe that methotrexate is a part of the indication for pegilodecase. That's probably why you want to use that or consider that. But as was said, other DMARDs will work here as well. Why not? What about URAT inhibitors?

Which one of you is working on URAT inhibitors right now 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 a post atenorad and dotinirad. Dotinirad is actually in use in several countries in Asia.

They both look a little more like benzromarone than anything else. And the preliminary data looks pretty good in terms of their efficacy. We're waiting for phase three to confirm that and to look further at any safety signals.

These drugs work by blocking urease reabsorption. That was the MOA for lisinirat that went on the market and off the market. That's right. Who wants to tell that story?

What's different? What's different is pharmacokinetics to some degree, sort of onset offset binding, different properties of how you interact with Uriat-one, how long it's if there's a burst of urine into the kidney. I think there's a good likelihood that at high enough doses, any of these drugs are gonna have some renal toxicity. I don't think that's gonna be very unlikely, but trying to find the right dose and particularly thinking about slow titration, possible combinations, there's gonna be ways with these more potent agents to use them hopefully more safely and to see some real benefits. 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 of the kidney. Lisinirad ostensibly came off the market because of a few rare cases of hepatotoxicity, and because of percentage ten to fifteen percent of patients on higher dose lisinirat alone developed a rise in the serum creatinine. But I don't think that that was why my colleagues didn't use lisinorad.

I think it was lack of interest, lack of aggressiveness about treating uric acid, to 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 lisinirad to actually be effective at lowering uric acids and better managing gout wasn't all that great until you combined it with allopurinol.

Oh, it was better with allopurinol, but the numbers alone weren't bad. I mean, got uric acids below five in a reasonable percentage of patients, Although you had to use the higher doses, 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 on from a current publication and basically says that, you know, we're either, you urate know, lowering, we're going after inflammation, we're going after the kidney with URAP1s. Anybody wanna talk about where gout is going in drug development? Anything that's new that we haven't There's

a couple of things we didn't talk about. One is the new NASP, which looks exciting based on its data. It looks equivalent to pegilodecase without immunomodulatory therapy. We need more uricases. We'd be interested to know whether could we give that to people that have failed pegilodecase?

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 generated. 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 a combination of urine like 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 LRP free inhibition, very important in gout and associated comorbidities.

I think that this really severe patient who needs peglodecase but has had a reaction to it, there is reason to believe that SEL-two twelve, also called NASP, may be a good alternative. The antibodies that form against pegglodecase are 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 to patients who can't handle peglodecase, 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 important the age, the older the patient, the more responsive they are to a uricase over the age of 15.

That's interesting. Again, in NAST, one of the moieties is sirolimus, is a calcineurin inhibitor, which is 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 you for enlightening us tonight with a lot of new information that's gonna 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's other things that are up on the website that you may not have seen, cases on gout called cutie clinics and a series of videos that have to do with gout as a systemic disease. We have Doctor.

Fisher 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.

Thank you.