STEP Talks from RNL26 Part #1 Save

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Our next great speaker is Doctor. Tahina Nyogi from Boston University. We asked Tahina, who spoke here before, did a fabulous she'd be here, except she's on a plane coming back from Europe right now. So she's recorded her presentation on disease modification in osteoarthritis. Doctor.

Niyoji.

Hi everyone, thank you for the opportunity to talk to you today about disease modification in osteoarthritis, why we failed. I'm sorry you can't be there in person, but I hope that I can join you at a future time. These are my disclosures. So first, why should we care? I want to first start with the burden of osteoarthritis.

According to the latest global burden of disease, about six hundred million people worldwide have osteoarthritis, reflecting about ten to fifteen percent of adult populations. The knee is the most common site of symptoms and in any given thirty day period about thirty percent of adults report experiencing knee pain. Now knee osteoarthritis often begins as intermittent activity related pain such as with weight bearing activities, but over time the pain becomes more severe and more persistent even with non weight bearing activities. In The US, joint pain and arthropathies are the number one reason for doctor's office visits, the majority of which is due to osteoarthritis. Worldwide musculoskeletal conditions for which knee osteoarthritis is among a leading cause is, the second leading cause of years lived with disability.

And then finally in The US, osteoarthritis is the third leading discharge diagnosis from hospitals. And this is number three after childbirth related hospitalizations and sepsis. And this was surprising to me, because I would have thought that cardiovascular disease, MI or heart failure would be higher than osteoarthritis. But this of course is due to all of the elective admissions for joint replacement, highlighting the huge burden of osteoarthritis on healthcare system and highlighting that to date we have no approved disease modifying treatments. So huge public health burden.

So why haven't we gotten to disease modifying treatments yet? Well, one conundrum has been this so called structure symptom disc discordance where some knees have pain, but not much going on in their radiograph and some radiographs look terrible, but there's not much pain. So the overlap between the two is not complete. And this has led a lot of questions about how much does pathology contribute to symptoms in osteoarthritis. But we have empirical evidence that structures do indeed contribute to knee pain.

For example, in this study, which was conducted by two orthopedic surgeons who happened to be brothers, where one brother conducted an unanesthetized arthroscopic evaluation of the other brother's knee. And we can only guess as to which one was the older brother. So what they did was the one brother interrogated various tissues throughout the knee and they scored how painful the tissue was. So the infrapatellar fat pad, ligaments, outer aspects of the menisci were painful, healthy cartilage was not because we know that healthy cartilage is anural. They did not interrogate the bone because we know that bone will be painful such as in a fracture.

And one of the first studies that I did was trying to disentangle why are we having such a hard time identifying the structure symptom relationship? And so we understand that if we exert a force punch on one person and the same force on another person, they're going to experience it differently, because of genetics, how much they slept, body mass index, mood, etcetera. And so one of the first studies I did in this area was to take an epidemiologist perspective of trying to remove all of those between person differences, those confounding factors and concentrate on studying people who have pain in one knee and no pain in the other knee. And in this way, all of those between person differences such as genetics, mood, BMI, etcetera, are inherently controlled for in that given individual. And so if there's pain in one knee, there must be something in that knee that's contributing to pain.

And when you do this kind of analysis, you find a very strong relationship between structure and symptoms. So we know without a doubt that structure contributes to pain, but in understanding that there's a lot of between person differences, we know that a lot of other things contribute to pain. And over the years, we've learned a lot more about pain sensitization about various genetic contributors to pain. But those of us that are clinicians also recognize that, we need to address someone's sleep, their mood, their physical activity, their coping skills, catastrophizing. And then there's a whole host of sociocultural expectations and how we experience pain and how we articulate that experience of pain.

And how much each of these contribute to someone's experience of pain differs. The other complicating matter in osteoarthritis is what to target. We understand that osteoarthritis is a disease of the whole joint. It's not just cartilage and bone, but all of the tissues in the joint. And over the past several decades, a lot has been understood about the various molecular pathways that are contributing to the pathology of osteoarthritis.

So there's been a tremendous amount of effort in trying to understand what pathways to target. But there's been a number of challenges in drug development and testing in osteoarthritis. So, while there's a lot of pathways understood to be important in the pathophysiology of osteoarthritis, the challenge has been in how to test those targets. A lot of animal particularly rodent models, are done in young animals, which does not truly reflect osteoarthritis as a disease in humans of older adults. And when animal models that have been aged are tested, they often show different findings than the studies that were done in the younger animal models.

Additionally, a lot of animal models don't adequately reflect human OA. For example, they might use a very inflammatory instigator for joint pathology, and that post inflammatory phase is what studied as Human OA isn't always post inflammatory, that's only a very, very minor proportion of people who have OA. Similarly, a lot of animal models use an injury model, which again post traumatic OA is only about ten percent of OA. So our animal models aren't always fit for purpose, and then what they are measuring may not always be completely applicable to human OA. Nonetheless, there are a number of animal models that have shown very promising targets.

So now we go on to testing them in humans. So we've got this promising pathway and who do we test them in? We test them in individuals who have Kellgren and Lawrence grade two or three, or sometimes even Kellgren and Lawrence grade four. And so Kellgren and Lawrence is the validated grading of radiographic severity. And Kelvin Lawrence grade two is the definition of definitive osteoarthritis.

So, a knee has to have Kelvin Lawrence grade two or higher and a certain degree of pain, usually above four out of 10. So we've got a lot of molecular pathways acting in the disease process. We've got a need that has established radiographic OA with some degree of pain severity. And this is often occurring in a person who's obese and may have malalignment. So already you can see that, you know, it's going to be challenging to target a single molecular pathway in an established disease with established disease, where there's a whole host of additional factors that are contributing such as obesity and malalignment.

And over the past decade or so, there's been increasing concern that the way in which we're testing targets is in knees that are too far along their disease course. And the horse has already left the barn. We can't close the door. We can't get the horse back in. So there's international efforts to, develop criteria to identify knee osteoarthritis prior to development of established radiographic OA in hopes that testing interventions in earlier phases of disease will prove more successful.

And this has been done very successfully in rheumatoid arthritis when the twenty ten ACR ULA RA classification criteria were developed. It enabled trials to be conducted at a much earlier stage of disease as one example. But beyond identifying NEO at an earlier stage, we also have to think about what's the target doing. And just simplistically, for example, if a target is anti catabolic, meaning simply trying to minimize the breakdown of cartilage, for example, then we need to make sure we enroll knees that don't have a lot of cartilage breakdown to begin with, because there's going to be very little left to prevent breakdown of. On the other hand, if there's an anabolic agent, one that's going to promote cartilage growth, then we need to make sure that there's an adequate variation in how much cartilage is there to be able to show that the cartilage is indeed regrowing.

The other issue is that a lot of the targets have been very focused on cartilage, so very chondrocentric and there's a whole host of other tissues that also need to be tested for targeting. And so, chondro protection as a major focus may not be so fruitful, particularly as cartilage turnover is very slow, whereas bone, for example, has a much higher rate of turnover. And now the other challenge has been targeting the mechanism of interest to the right patients and in identifying the relevant endotype. We know that there are a number of different pathways that lead to osteoarthritis. Here I'm showing these different tributaries all emerging into the river.

So osteoarthritis radiographically established osteoarthritis is that river that's been arrived at by all these different pathways. And so right now our trials are sort of all comers, Kellerman Lawrence grade two or higher with pain severity four out of 10 or higher. And we're likely missing the signal for the noise because ideally if we had the right endotype, we'd only enroll, for example, people that are green, because then we'd really be able to identify these signals. But right now with small phase one, two trials and all comers, we're likely missing the signal for the noise. I've talked about structure, but let's go back to pain.

You'll recall I just said a few slides ago that pain is multifactorial. So if we are enrolling someone with a pain severity of at least four out of ten, what does that mean? Now, if we have an OA target that is targeting some molecular pathway that is causing structural pathology and is also thought to be important for OA nociception, we want to try to match the pain mechanism to the likelihood that they're going to respond to this intervention. So for example, I have these four hypothetical people, the lightest blue is oenociception. And then we've got contributions from sensitization, psychosocial factors widespread pain.

So in person one, only about ten percent of their pain is due to OA nociceptive pathways. Whereas persons three and four have the majority of their pain experience being related to that OA pathology, the molecular pathway that's being targeted. So we want to enroll not only the person for whom the endotype is that molecular pathway, but also that the pain experience is largely related to that pathway. So we would want to enroll person three and four to increase our likelihood of being able to show a signal for targeting that pathway, not just structurally, but also symptomatically. Whereas if we were to enroll person one or two, even if the structural pathology improves, or we can show a difference versus placebo, if their pain is not related to that pathway or the majority of their pain is not related to that pathway, we're not going to succeed.

So, then we come to trial feasibility as well. OA is a slowly progressive disease. It can take years for progression of the structural pathology. And so, while symptoms we might be able to test over a short period of time, depending on what we're testing, for example, NSAIDs can be tested in a thirteen week trial, no problem. But if we're trying to get at a disease modifying agent, it has to affect the structure and symptoms.

And this is really important because this is different than many other rheumatic diseases where the regulatory requirement is that the intervention improve the way the patient feels, functions and survives. So in OA, there have been some interventions that have shown decreased joint space narrowing, for example, but did not show any improvement in symptoms. That will not get regulatory improvement. It has to show both structure and symptom together to be considered disease modifying. So, if we have a very slowly progressive disease, we can't do a trial in just a few months.

It's going to take years. And typically, one and phase two trials are much smaller sample sizes, but if you have a very slowly progressive disease, you're going to need a much larger sample size. So, if you have a longer trial duration and a large sample size, you're going to need a lot more money. Unfortunately, many phase one, phase two trials in osteoarthritis have either been short duration or small sample size or both. And so, I fear that we've probably missed out on some promising targets because of these trial design issues.

And I'm going to give you two examples from IL-one beta inhibition and colchicine in osteoarthritis. Both have been studied in knee osteoarthritis and colchicine has also been studied in hand osteoarthritis with no positive studies. These studies have typically been small sample sizes and short durations. Now along comes our cardiology colleagues who have been interested in, targeting inflammation for cardiovascular disease. And there were two trials, of, these agents, canakinumab is an IL-one beta inhibitor and then colchicine.

The CANTOS trial, the one on the left had about ten thousand participants with cardiovascular disease and the colchicine trial had about fifteen hundred, sorry, five thousand five hundred participants. That's the low dose two trial. And both showed positive cardiovascular endpoints. But what was really interesting, particularly for Kantos is they recognized that there was some kind of a signal for joint replacement. Now the vast majority of joint replacement is performed for osteoarthritis.

For the knee it's about ninety seven to ninety eight percent are due to osteoarthritis, for the hip it's about eighty five percent. And what they found first was published the Kantos post hoc analysis followed by the Ludogo two post hoc analysis. They both found the same effects, about a forty percent lower risk of having joint replacement in the treatment arms compared with placebo. So this is providing some proof of concept that IL-one inhibition, IL-one beta inhibition and colchicine have some kind of modifying effects on osteoarthritis. Is it structure?

Is it symptom? Is it both? We don't know because joint replacement, occurs in people who have advanced disease, but they're symptomatic. But nonetheless, this provides some illustration of what I just mentioned that I think we've been missing some promising targets because of the way in which our trials have been done with small sample sizes, short durations, and kind of all comers heterogeneous samples where we miss the signal for the noise. Whereas in these cardiovascular trials of 10,000 people, five thousand five hundred people followed for four years, five years, they're able to find the signal despite that noise.

The other challenge we have in osteoarthritis trials is, how do we measure our endpoints? We need to measure symptoms, we need to measure structure. So for symptoms, we have a number of different validated instruments here, for example, numerical rating scale, but most typically use the WOMAC or CUSE. Now, over a twelve or thirteen week NSAID trial, an NRS numerical rating scale WOMAC works perfectly well. But what about a trial that's one year long or five years long?

How do people report their symptoms over a longer period of time? One of the challenges is that when people have symptoms, they often accommodate their activities to maintain a level of symptoms with which they can function. So what they might have come into the trial with as four out of ten, a year or two later as their disease progresses, a couple of things can happen. One is they can say my pain is four out of 10 today. And you say, well, it was four out of 10 a year or two ago.

Oh, back then my disease wasn't that bad. I really didn't understand. My pain really, I would have probably said it was two out of 10 at that time if I really knew what my disease was going to become like. So that's one thing is frame shifting. And then the other is, oh, it's four out of 10 today, but I'm not climbing stairs anymore.

I'm not walking a block to the grocery store, etcetera. So they accommodate their physical activity, what they're doing. So a pain rating is difficult to interpret in isolation and when you're trying to follow these trials for five years, especially placebo controlled, that's challenging. Placebo controlled for that long for symptoms is challenging because people are going to use all sorts of other options, including rescue medications, but also medications you might not even be capturing to manage their symptoms. So that's one challenge.

And the other challenge has been previously radiographs were used as trial endpoints. And radiographs, again, slowly progressive disease radiographs change very slowly, progression occurs very slowly. And also positioning is very, very challenging in radiographs to detect or to measure those changes and a slight rotation can make it seem like there's been progression when there hasn't been. So MRI, we have MRI, great, why can't we use MRI? Well, to date the regulatory agencies have not accepted MRI findings as being yet validated.

So there's ongoing international efforts to validate structural endpoints on advanced imaging such as MRI. But again, as I mentioned, regulatory agencies require that there be not only structural benefit, but it has to be tied to symptomatic benefit. And so again, lots of international efforts are ongoing to optimize trial endpoints and their measurement for OA trials. So, where do we go from here? What is the future of OA management?

I'm very optimistic and hopeful that we will have an approved disease modifying agent in our lifetime, But it's going to take a lot of work and effort and there's a lot of international efforts ongoing to address some of these challenges I've mentioned. But I do think that there's not going to be one single magic bullet. I think osteoarthritis management will have to be multimodal, not just pharmacologic, but also addressing all of the other things that contribute to not only structural pathology, but also symptoms. Healthy weight, physical activity, malalignment, sleep, mood. Did I say physical activity already?

Optimizing biomechanics, etcetera. It's going to be, have to be multimodal. And this is not novel. We just need to look to our successful cardiovascular colleagues who've really managed to reduce the burden and mortality of cardiovascular disease. They don't use a single magic bullet target for managing cardiovascular disease.

They also use multimodal management, hypertension, diabetes management, weight management, physical activity, smoking, cholesterol, etcetera. And so I think that's where we're going to have to go. But first we need to get some promising, treatments to enable us to actually get to that future of multimodal management that will include being able to halt disease, structural disease progression. And so eventually our trials will need to target the right patient at the right time in their disease with the right intervention or plural interventions. With that, I thank you very much and I'm sorry I can't be there, but I'm happy to take questions by email or through various social media.

So, you very much.

Okay, thank you very much. All right, it's break time. Let's be back here at 11:05 for our next session on advancing practice.

We're next going to move to our step session. These sessions are kind of a mix of medicine and history and science and just sort of meant to be informative, and we thought it would be really great to take advantage of having world's expert on gout, Doctor. Bob Turkleftab, talk to us about a disease with an incredible history. Maybe we should have done it backwards, because you already heard him talk about so many exciting things going on in gout, whereas for a

while there hadn't been anything, but now he's gonna tell us why we should be so excited about all the exciting stuff the area talked about. Bob, welcome. Thank you. Okay, here are my disclosures. So we always learn lessons, we hope.

The lessons from the gout epidemic in England is where I'll start. I won't start with Hippocrates, or Galen, or the others. And that epidemic involved wealthy males, obesity, consumption of British West Indies sugar, as you can see in Britain, in England rather, at the time. Very high sugar consumption in France, nothing for and William Wadd said for one fat person in France or Spain, there are a 100 in England. You see the names of pubs here.

And low level lead poisoning from the port wine. So a perfect storm. And interestingly, the biology of this is that fructose metabolism chews ATP, and some of that ATP gets into the purine degradation pathway and produces uric acid. And alcohol, actually there's an exchange mechanism via URAT1 and lactate and alcohol inhibits uric acid excretion in the kidneys and also when you metabolize alcohol you chew up ATP and some of that ATP is degraded to uric acid. Whereas with wonderful coffee, it's an xanthine oxidase inhibitor and associated with less frequent gout.

So sugar and alcohol, major promoters of hyperuricemia, a familiar story in this year. And this is the two hundred and fiftieth year of The United States. So I wanted to show you that The USA gout epidemiology two fifty years ago spilled over from England. What a coincidence, we broke off from England but we got gout. And seven out of the fifty six signers of the Declaration of Independence had gout, including Benjamin Franklin who as you know went to France for quite a while.

They were using colchicine over there and brought it to America and it was the first pharmaceutical development of colchicine in America. And his famous quote was, Be temperate in wine eating girls and sloth or the gout will seize you and plague you both. He, I guess, said this out of experience. So what we have now, way ahead to the future, is a democratization of gout and hypouricemia. Gout used to be called the disease of kings and the king of diseases.

Now it's everybody's disease. And so unfortunately, the prevalence of gout has risen to about five percent of USA adults. It's over twelve million people in The United States. It's tripled over the last four decades, and also increasing and increased globally. And it used to be nine to one male to female, and it's a lot less than that now, And it affects about five percent of elderly USA women not involved in sloth or other debauchery.

Asymptomatic hypuricemia, about one fifth of our population. The mean serum urate at the turn of the century around 1900 was closer to three and a half or four, and now it's five milligrams per deciliter in women and six in men. Very close to the saturation threshold of uric acid, which in physiologic solution is about 6.8 or seven milligrams per deciliter. And then what's also happened is gout flare hospital admissions have doubled over the last two decades, whereas admissions for flare of rheumatoid arthritis have gone down over fifty percent. So gout is rising, and we need to do something about that.

And then we have a perfect storm of factors here that lead to this epidemic really, this growing epidemic of gout, including genetics, a genetic influence in about forty percent of gout cases. The rest of the gout cases, life happens is what happens there. Ethnic demographic changes in The United States, socioeconomic and racial factors, and a surge of urate elevating and inflammation mediated comorbidities, including hypertension, which is just raging, CKD, which is raging, hyperlipidemia, coronary artery disease, heart failure, obesity, which is raging as we've heard, metabolic syndrome, type two diabetes, raging, and MASH, which was unheard of, not in any medical textbooks in the year 1900, and now is the leading cause of liver transplant. And people are living longer, and as they live longer with high urate levels, they get more gout. And then how do you treat hypertension?

Well, diuretics are great antihypertensive, so we have to deal with that, as well as many drug interactions and complex medical decisions. So this is current history, and you can see that the epidemiology here from 2001 to 2021. A massive upward trend of the gout burden in the 10 most affected states. You see how color coded they are, and Texas has a pretty brown color here. And so we've got a real problem on our hands.

So guess what? So the Britain epidemic, the England epidemic years and years ago was ignited partly by sugar. And in the year 1900, people had four pounds of added sugar per year in their average American diet. And I talked about the fact that the MAH prevalence was about zero. It wasn't written in any textbooks.

And in 2025, 66 pounds of added sugar added to the usual carbohydrates that we have in the average USA diet. This is what 66 pounds of sugar looks like. Added sugar, that's what it looks like. Can you believe that? And then basically all these people with BMIs of greater than 40, body roundness index numbers probably more accurate than BMI, tremendous amount of obesity.

And our children and teens are overweight and obese. That's tripled since 1960. And so the culprits are not limited to these things, but sugar is a humongous influence here. So what the history of gout treatments? Well, we already heard a question about high dose salicylates.

High dose salicylates are uricosurics. And in the old days, that was like reserpine for hypertension, basically. Allopurinol was developed, basically, believe it or not, to improve the efficacy of six mercaptopurine in treating cancer. It wasn't developed to treat gout. Now, know that that's a very bad drug interaction, including with azathioprine.

And it was approved in 1966. Hydrochlorothiazide, chlorothiazide, they were approved in 1958. So that gives you some perspective. Probenecid was developed to increase the circulating half life of penicillins, and that was needed for the various infections of the age. And they discovered that it was uricosuric, so that was a repurposing event.

Cortisone won the Nobel Prize, discovered to get people with gout flare on their feet again. And here's when indomethacin was approved. Hopefully, in some day in the future, all of these drugs will be obsolete because you know there's problems with each of them. And then colchicine was grandfathered, it was a grandfather approval without clinical trials way long ago. And basically there was a big gap and then people started to think about doing things better.

So febuxostat is a channel inhibitor, allopurinol is a substrate inhibitor of xanthine oxidase approved in 2009. And then peglodecase was approved in 2010, very selective therapy, but instead of putting the uricase in the liver, which is not easy to do, having it in the circulation is a wonderful and beautiful thing if it's working because you're degrading every molecule of urate that enters the bloodstream twenty fourseven, three sixty five days of the year. And so it's like a giant Hoover vacuum cleaner cleaning out all your urate. So its use is when it's effective is transformative. And then can Akinumab, because of the discovery of the NLRP3 inflammasome IL-one beta pathway, so effective in treating and prophylaxing gout approved in Europe in 2014 and approved last year in The United States.

Now, despite the long history of urate lowering therapy, the first ACR gout guideline was in 2012, the first in seventy five years of the ACR. It endorsed treat to target urate lowering therapy. It also endorsed HLA B5-eight zero one testing. I was the senior author of that guideline, and it's held up pretty well. Lisinurad was a spectacular failure as the first sort of highly selective uricosuric drug.

It caused acute kidney injury as monotherapy, and illustrated the risks of that target. But this drug was imperfectly formula developed. And now, Dotinurad, which is derived from benzbromerone, a drug that's approved outside The United States but in very limited use. It was approved in four Asian countries. It's a highly selective URAT1 inhibitor.

And uricosurics are at the forefront of developing these highly effective selective URET1 inhibitors that are very potently uricosuric. That's also we talk about what happens in terms of diagnostics and the classification of gout that improved a lot on the 1977 classification was the ACR ULA classification of 2015, and we'll go over that and why it's so important. But it goes hand in hand with the adoption of ultrasound and dual energy CT diagnostics way back in 02/2009 to help us pinpoint the presence of monosodium urate crystal deposition in tissues. Whereas before we relied on the demonstration of urate crystals in joint fluids as the gold standard. So that's the history.

Now, there's another thing that happened, and it used to be thought that colchicine was only effective for acute gout flare to the point that people got diarrhea. They called it dose to diarrhea, or dose till you diarrhea, and it was the standard of care for treating the gout flare with colchicine, giving one point two milligrams and then zero point six milligrams an hour, until the patient got sick to their stomach and had to run to the toilet with diarrhea in eighty percent of people, or reached the maximum dose, which was twelve tablets, or got miraculously better. And so gout patients used to be drowned in high dose oral colchicine in that protocol. But in the AGREED trial, 2010, a really unique design, and using low dose colchicine, high dose discovered that the maximum concentration, the Cmax, in blood was the determinant of the efficacy of colchicine, whereas the area under the curve for the high dose colchicine here, a lot of exposure, was the determinant of the side effects. And so this really revolutionized using low doses of colchicine to treat gout flur has revolutionized the treatment of gout flur with colchicine.

The preliminary criteria of the American Rheumatology Association at the time for diagnosis of gout demonstrated that they didn't use ultrasound or tool energy CT, and they relied heavily on clinical features and some other things to come up with this set of criteria. And looking at these very sensitive and specific features of ultrasound and then dual energy CT rather than just erosions which take on average five years to develop in the average gout patient is a big advance in the history of gout. And you can see in the 2015 ACR classification that feeling a TOFIS, a score of eight or more classifies a patient as gout, that feeling a TOFIS is worth four points, but actually seeing a TOFIS by ultrasound or DECT or joint erosion on x-ray that's characteristic of gout is worth the same. So this has really improved how we do clinical trials and impacted on how sure we can be of diagnosis in the clinic. So basically, it used to be that the drugs that we used were all antiquated, non selective, and potentially toxic.

So it's the toolkit of colchicine, which can kill people, has lots of drug interactions, difficult to dose in CKD, and difficult to dose above zero point six milligrams a day in long term prophylaxis. A lot of people, about half get diarrhea and lower the dose. NSAIDs, which are hell on wheels, right? And then corticosteroids, all of these drugs, non selective and toxic, and then all of these drugs, allopurinol, many issues, afebuxtet, black box warning for cardiovascular disease and probenecid, lots of drug interactions, GI intolerance, limits in using in CKD, pretty useless in clinical practice these days. So where do we get our new impetus in drug development?

Well, a lot of it's the big bang of looking at gout genetics. So those of you who went to med school before about maybe ten years ago, you always had these questions in med school and on the board exams. The patient has gout and the answer is that the patient has HPRT deficiency, you know, uric acid overproduction. They were thinking that that was really like the most important genetic abnormality in gout was purine metabolism, inborn errors of that purine metabolism. And it was shown that by these genome wide association studies and these Manhattan plots, that it was urate transporters consistently across all these different populations had the big associations with the genetics of gout.

So it's people that can't get rid of the urate properly by renal means or by GI means when it's an ABCG2 mutation, and then the kidneys are taxed to get rid of all this extra uric acid, that this was the big driver, genetic driver of gout. And you see that reflected now in the development of these highly selective URET1 inhibitors that can get the serum urate below five in a vast majority of patients and below six in eighty percent plus of patients and basically with very few titrations do that. So this is the future built by the history of looking at the disease. And basically that's what we've got is a lot of transporters being targeted for the next wave of drugs to treat hyperuricemia. So appreciate your attention.

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