Librela discussions part one - Prof John Innes

(upbeat music) - Welcome everybody to the BVW podcast with me, Simon Ratcliffe and me Duncan Bout. And tonight we are delighted to be joined by a true legend of our field, Professor John Innis. Good evening, John, how are you? - Good evening, both of you. I'm absolutely fine. Well, a little bit tired of being in theater all afternoon, but I'm fine. - It was a very impressed you did a wife rapture today and if I was doing surgery of that magnitude, I would be rocking in a chair right now, but you're on our podcast, so a very impressed and appreciative. So thank you for coming along anyway. - Well, you press gang me into, I didn't have any choice, Simon. (laughing) Here I am. - So as probably everyone knows, John has recently published a very interesting paper on bed in vet map for Lidrella as the trade name is here in the UK, which we'll be discussing with him shortly. But first, John has had Julia fascinating career in orthopedics and we'd like to hear more about that. He is one of those guys where you do a bit of research about his career and it made me wonder what on earth I've been doing with my own life really. So graduated Liverpool 1991, moved to Bristol and over 10 years, you did a PhD in osteoarthritis, a certificate in veterinary radiology as well as gaining R-CVS specialist status. So that's a good 10 years after graduation. Did it feel like that was you in a hurry or was that a natural progression and you just loved orthopedics and you just throwing yourself into it? - Yeah, that's a great question. And I'm trying to think back to the younger me, but I had a great boss when I went to Bristol, Vex school, that was Steve Butterworth. And Steve was only a few years older than me, but we got on really well and Steve was full of energy. He taught me a lot as did other people at Bristol. Even before arriving at Bristol, they rang me up and said, "We're gonna register for the certificate in radiology." So I didn't really have any choice other than to get on with postgraduate exams and back then radiology was the one certificate you could do as a new graduate. So I did that and actually that was really useful and because he gives you a broad perspective on veterinary medicine and surgery, I didn't think I'd ever do a PhD, but I sort of got the bug a bit by working in Bristol Vex school. And I was really lucky I went to do my PhD with Professor Paul Deep, who's professor of rheumatology in Bristol, then who's a world renowned rheumatologist and really interestingly, just before I started my PhD, he'd come back from being a hostage in the Gulf War. So he was on the British Airways plane that was stalled by the Iraqis and he was taken hostage for six months in Baghdad. He went through life changing experiences and clearly changed him as a man, but changed him for the better. And he was an absolutely inspirational leader. And many of us benefited from his energy and his enthusiasm. So I had a great PhD, really enjoyed it and then I went back to Langford as a lecturer. So yeah, it was a good time. And why all the pedics then? Did you know as an undergraduate that you loved all the pedics or how did it become orthopedic straightaway? Yeah, that's interesting. In fact, it's a BVOA podcast. And I was sort of there at the rebirth of BVOA back in 1990. I was doing my student elective in Liverpool with Dave Bennett and Chris May. And I remember them coming in saying, "Oh, we're thinking of working with Stuart Carmichael to get the BVOA off the ground." Because it had been the orthopedic study group prior to that. And then that sort of folded. So yeah, I was kind of there. I was interested in orthopedics because not only was that pretty strong at Liverpool and other things weren't at the time. But my local practice where I did EMS, had Malcolm McKee, Peter Renek, and then Stuart Carmichael as the surgeon. So it was just a great place to be as a student. So that kind of got me enthused about orthopedics. And then in 2001, you went back to Liverpool to become professor of surgery. And that's where our paths crossed. So I was an undergraduate around that time. So this isn't to make you feel old. I think you were extremely young, professor of surgery. But I have a date for you. I wondered if a date meant anything to you. So my final vivery exam, which John was in. I looked at the date today, 26th of May 2005. I wondered if that date rang any bells. Well, you're not that related question. Anything else going on in your life around May 2005? Yeah, absolutely. 2005. That was the Champions League final in Istanbul. And Liverpool, one of the most famous games ever because Liverpool came from 3-0 down to win that game. And I would have been in Istanbul if it weren't for you not having final exams and I had to be a Liverpool. So I still blame your year for missing out on one of the best football games ever. Well, the side for us was that no one did any revision the night before because it was one of the best games ever. As he said, Liverpool's football match, so everyone, their football fans or not, was watching the game. And then I distinctly remember walking into my vivery exam, not feeling particularly confident and seeing you sat there with a massive grin on your face thinking, "There is no way he's going to fail anyone today." That's what it's called. You caught me in a very good mood. Let's put it that way. Yeah, no, that was brilliant. And then, so you stayed at Liverpool to 2013 and then you moved into the corporate world as a referral director for CVS. Just wondered how much clinical stuff were you doing in those years or were you mainly managerial sort of oversight at that stage? Yeah, that was sort of change. I mean, CVS sort of contacted me and asked if I was interested in a new role for them which was developing specialist referral services within the company. And but I did insist that I said, "Look, I want to stay clinical." And I'll be honest, that was a sort of defensive move really because I thought, "What if this corporate thing goes completely peat-tongue?" And our USP, especially, is our clinical expertise. So I always maintained, although the amount of clinical work that I did did sort of decrease over time. And in 2020, I became chief veterinary officer for the group and then COVID hit. And that was awful for many, many people. I certainly didn't enjoy it. I was then in charge of COVID clinical policy for the whole company, which was at that time sort of 6,000 vets and 500 clinics. And I always stopped working from home, which I hated. But I perfectly accept that COVID was much, much worse from many other people. But so yeah, I, and there was a leadership change, which didn't really align with my values. And so I've started making plans to get out really. So in the middle of that, I must mention you, president of Ezvot, 2014 to 2016, and became fellow of the RCDS, involved in over 100 peer review articles and book chapters, which is quite something, John. And then that wasn't enough in 2022. Co-founded an independent referral practice based in Chesha, and now with a second branch in the Midlands movement referrals. So how's that going? Obviously, how do good case today is it? How's the new site going? I'd all go really well. I'm really enjoying it. And actually, it's now that I'm grateful that when I was in CBS, I insisted on continuing with clinical work, because I'm back at the coal phase doing more clinical work. But for the first time in my career, I don't have a boss, other than Mrs. Innis, of course. But so it's actually really liberating. And I've got some great colleagues. And there's four other directors in the business, three of whom are clinically active. One is investor of that from the US. We all go on great, and we're really enjoying the ride of growing the business, and it's going really well. Yeah. (upbeat music) - One of the things that you've done throughout your career is a contributed huge amount to the veterinary literature and being incredibly valuable to all of us to have that work available for us in evidence-based. And one of the most recent contributions that you've given us was paper you published back in March 2025 on the Braille. So we're hoping to spend a lot of this podcast talking about the Braille, which is obviously there's some controversy around and I guess a certain amount of debate within the profession. So just to introduce the paper that you published, along with Duncan The Cells and another number of other authors. And this was a randomized parallel group clinical trial comparing Bedium Vet Mab and Meloxcam for the management of K9 OA. And that was published in in front of years. Just to sort of summarize the paper for our listeners who may or may not have read it. So it's a randomized open label clinical comparator study with 101 dogs slaughtering from osteoarthritis. no assigned to either receive daily or mollox cam, or subcutaneous bed-in-veh-mab administered on days one and 28 of the trial. Obviously, John, correct me if I get any of this wrong, but I'm sure it's all good. So, hopefully quoting directly from your player. And then the dogs were assessed baseline, and then every two weeks up until 56 days. And a fixee was compared at each time point between the groups using a validated metrology instrument, the canine osteoporitis index. And that verse effects were recorded during the study period. So, fairly short-term study period. I guess the first question is how did you get involved in that study? Was the, what was the impetus to try to do that work? Yeah, so I guess because of my background in OA research over the years, over the decades, I suppose, most of the research funding that we were able to attract actually came from industry. And I think we have to remember that actually, that there's not a lot of money around in veterinary research. And industry has been kind of key in funding a lot of that research. Now, clearly they have their own agendas. But we've gained an awful lot alongside that funding, you know, as side projects and things, because the funding employs people. So, yeah, I'd worked for various companies over the years. And then I mentioned that I decided to leave CVS and I did that resigned. And I had a period of time where I was self-employed. And it was serendipity really, because I had contacts at Soetis. And they actually heard that I was available. And they contacted me and said, well, we're thinking of doing a clinical trial. Could you help us with it? So, I agreed to do that. And so I did the study design for them initially. And Duncan LaCells helped me out a bit with that. And we submitted that to them. And we discussed it and they agreed it. So they funded that study. But it was delivered by me. And I had a contract with Soetis. And then I found a group of primary care vets in the North West. So that were happy to work with me. And, you know, they saw the cases. I managed the study remotely using a web app called Castor EDC, which allows the vets to enter data in real time on the clinical report forms. And allowed me to see the data coming in in real time on a dashboard. And there's a great way to run a clinical study. So that's the background to it really. You know, it may surprise people, but a clinical study like that costs in the region of, you know, £400,000. So these things are not cheap things to do. And without that level of funding, the trials just wouldn't happen. So yeah, I mean, I think the shortcomings of the study would be that A, it was open label, B, it's fairly short term. It's only eight weeks of treatment. And you're just summarising, you know, what the major conclusions were from that study. Yeah, so we have to remember we're going back sort of three and a half years when we were designing the study now. And we knew a lot less back then, particularly about Librella. But we powered the study for efficacy. And that was our primary interest in the outturn. And we used the canine orthopedic indexes, the primary outcomes measure, or the change from baseline in the COI score. We showed no difference in efficacy during the study. But both groups had significant improvement over time. But there wasn't a difference between Meloxicam and Bedin Vet Mab. And then we did of course record any adverse events. You know, we saw, I think, 17 adverse events in Meloxicam group. And the most common was gastrointestinal system upset. No surprises there. The rate of GI adverse events that we saw was in line with published adverse event rates for Meloxicam. And we saw four adverse events in the Bedin Vet Mab group. And one of those was Polydipsia, which is now on the data sheet as a rare side effect of Librella. Yeah, I think certainly when I think about lots of studies that have read over the years, introducing new non-steroidals, a lot of the time it will be in comparison to an existing non-steroidal. And it's a sort of a non-infavorioreal type study. And so it seemed to me reading the paper that it was designed along that kind of line, that it was to show whether it has a efficacy, but also to give an idea to people who are very familiar with non-steroidals, what the degree of efficacy was likely to be in comparison to that. It's not necessarily trying to show that it's massively better. It'll, you know, love to see that drug that's infinitely successful, but primarily it's showing that it does work. I think that's an important thing for us to take away from the studies we so far have available is that I think most of us would recognise Librella does have a efficacy. Yeah, I mean, it's interesting that lack of efficacy was also recorded as an adverse event. And I'm going from memory, I don't know the paper in front of me, but I think we had two in the Librella group and three in the Meloxicam group. I think we'd all recognise as clinicians that not every dog responds well to either of these products. So we did have some lack of efficacy. And I think that would fit with my clinical experience with both agents as well. Yeah, that's fair enough. I don't really understand the science of how it works, particularly because it's this whole new agent of the pain relief. Can you, you should some light on that, John, just for us to understand it a bit better? Well, the mechanism. Obviously, it's new to most vets, of course, but if you look in the literature, research on nerve growth factor and joint diseases been going on for about 20 years. In fact, one bit of my career, you missed out, which was, I had six months as a visiting professor in Sydney and I worked in a research group there, an old friend of mine, Chris Little, who's a veterinarian. He was a boarded equine specialist, but then he went into arthritis research and he had some really good research group at the University of Sydney at the Colling Institute. And I remember him one day, I mean, he's a very curious individual, always looking for new information and he dropped a paper on my desk in this is 2010 and he said, I think you should read this paper. And it was a study looking at blocking the action of nerve growth factor with an antibody in a mouse model of osteoarthritis. Now, the lead author on that paper was Julia Ingles, who is an Australian veterinarian. Also on that paper was Professor Tony Vincent, who's Professor of rheumatology at Oxford. But it really struck me this paper because they were showing that they could return weight bearing in operated mice to near normal in the post-surgical period. And then the OA model in mice that's used most commonly is destabilization of the medial meniscus. And that predictably gives you end stage OA in about 16 weeks. And then when they delivered the anti-NGF antibody in the last part of the study, they could have pretty much abolished the OA pain in these mice as well. So I remember that paper very vividly actually and discussing with Chris because it was the first time I'd seen something really new that could block pain well in osteoarthritis. So that's 15 years ago. Actually talking to Tony Vincent recently, she said at the same time Pfizer were doing clinical trials around blocking NGF in human patients. So they were obviously ahead of the game anyway. And Manivus know the story of the clinical trials in human OA, which went on for about a decade because they were interrupted or suspended by the FDA and because of issues with frequency of RPOA. So that happened in the human field? I haven't answered you answered your question. No, you saw a tension on something quite interesting though that I just know about. So can you explain that a bit more? Yeah, so Liberella blocks the action of NGF. NGF nerve growth factors released from cells when they're stimulated such as macrophages, mass cells. We now know from Tony Vincent's work is also released from condrocytes. So if condrocytes aren't happy, they'll upregulate their release of nerve growth factor. And nerve growth factor is a mediator of pain. So it binds to its receptor, the track A receptor on nocysector. So nerve endings. And then that complex of track A and nerve growth factor is internalized into the neuron transported to the cell body in the dorsal root ganglion where it induces transcriptional changes and you see released of other neurotransmitters which are then transported back to the nerve ending and also into the dorsal horn of the spinal cord. So it drives peripheral sensitization and central sensitization. Was this interested about the human studies you said? So there were studying anti nerve growth factors for about 10 years and then they stopped because of rapidly progressing osteoarthritis on the human side. Where is that whole process up to now then? You know, well, yeah, I mean there were a couple of antibodies in development in human medicine. Tanasimab would be the most well-known. That was a collaboration I think between Pfizer and Eli Lilly. And hundreds of patients were in different trials. And they found in the outturn that patients that were on higher doses of anti-NGF had an increased incidence of RPOA, rapidly progressive OA, which is a previously diagnosed syndrome in people, it occurs at about a rate of 1% typically in older women, typically in the hip joint. But that rate went up to about 3% with high doses of tenazumab, and it went up further still to about 6%, and when patients were taking a non-staroidal antanazumab. And on that basis, the European Medicines Agency and the FDA decided not to give tenazumab a license. So that work has stopped. Interestingly, you know, talk to Tony Vincent, I mentioned she's professor at rheumatology at Oxford, she's written quite a lot about pain in OA, and you know, she recounts patients that were on these trials saying, you know, this is great, I'm back dancing, I'm doing things that haven't done for years. So it's an interesting perspective, she, you know, the regulators are conservative, but lots of patients were benefiting from the pain relief. There's an APR in the New England Journal of Medicine, which was one of the first studies that shows a really nice dose response to, in terms of analgesia from tenazumab. But clearly, the regulators made their decision and that work has stopped, and those companies must have spent millions and millions and millions and they've got nothing. There's some interesting, there is some interesting work around looking back at those patients that developed RPOA and looking at biomarkers that could predict those patients that were developing RPOA. So, obviously we'll come on to talk about the reports of joint related adverse events in dogs on treatment with Liberella. But my view is we need to understand what the rate of that, the frequency of that sort of adverse event is. If it's in frequent, which it may be, we don't know, then maybe, rather than throwing the baby out with the bath water, maybe what we need to strategies to understand and try and predict those patients that might be at risk, and maybe look at biomarkers that we could use in the clinic. It's the same way that we monitor patients on long-term, non-steroidal, we use routine tests to look at effects on kidney function or whatever, but there might be different tests and new tests that we might need to use. So, I'm interested, no, well, it's, this is why we've got you here to give us these insights really, and that's great. Do we really have a good understanding of what the role of nerve growth factor in bone remodeling is, and why we may be seeing some of the sort of significant changes in and around joints and with bone fragility that I think we're suspicious of? Yeah, well, you know, it RPOA in people in those trials, it comes in two forms, type one and type two. One of those is simply rapid loss of cartilage without osteophyte formation. And of course, in humans, they measure joint space width as a surrogate for cartilage thickness. We can't do that in dogs, because we don't take weight, being ready to go. The other form is sub-condal collapse in people. Now, at the moment, the phenotypes of what's been reported quite broad, and it may be that they're all relevant, but can break them down into subsets, perhaps, but some are very hypertrophic, and lots of almost extraarticular bone formation, whereas others with fatigue fractures that have been reported, others seem to be soft tissue instability and loss of joint stability. So I think we need to understand those. I think the other danger here is that librelas have been used so much in general practice. 28 million doses so far, I think, have been sold pretty much every dog has got joint problems. If they're getting worse, might end up on librela, and we've got to be careful, I suppose, to be critical, make sure we've ruled out differentials that we know about, and then those that are left that we cannot explain through other means. I think we need to really try and study and understand what's going on. Because there's no doubt, I think, in that case series that's been published, there are some cases in there that you cannot explain by other means. There's some others that, if you were a peer reviewer, you might challenge and say, well, you haven't necessarily ruled out this or that, but I think it's fair to say that there are some cases in there that we need to take seriously. Just to be clear with the paper we're referring to, I'm sure most listeners will know that it's Mike Farrell and his group published a study entitled, the Musculoskeletal Adversive Events in a group of dogs receiving bed and bed that. And it's a combination case series of dogs with a verse, Musculoskeletal events suspected to be attributable to the administration with bedrella, and also a review of the Musculoskeletal Adversive Events reports that had come into the European Medicine Agency. So we are in discussions with Mike and his group. We're quite keen to get a sense of their paper on the podcast as well. We feel like both papers are really fascinating and it's really good to have good information to go on. Duncan, do you want to talk a bit about that paper and pick John's brains on it? Yeah, of course. So there were some two parts to that paper. They were really looking specifically at the rate of Musculoskeletal Adversive Effects and comparing that between Librella and a group of non-steroidal. And they basically went back through the European Medicine Agency Adversive Event reports and sort of assessed whether or not they're being categorised correctly and raised some concerns about potentially Zoritas misclassifying some of those based on the opinion of the panel. And then they also presented a series of 19 dogs which had had Librella treatment and where they'd had this range of Musculoskeletal Adversive Effects from, as he described, John really severe progression of arthritis, so there were some dogs which had developed fractures which we perhaps wouldn't usually expect to see in the particular circumstances that the dogs were in. And I wonder whether in comparing the rate of Musculoskeletal Adversive Effects between Librella and non-steroidal, this orthopedic surgeons we're particularly concerned about this type of adverse event because it's in our area of interest and I think the last thing we want is to go and try to treat a dog for osteoarthritis and then find that actually, essentially, we have concerns that the treatment we've given has made things worse. I think it would be useful to look at the overall adverse effect in comparison because obviously one of the things that we're very used to with non-steroidal is a rate of gastrointestinal side effects which is perhaps underestimated in the adverse effect reporting. I wonder whether you feel that Musculoskeletal adverse effects are particularly of concern to us as orthopedic surgeons, whereas for colleagues who are medics, might be much more concerned about the adverse effects of non-steroidal because they would tend to see those cases and deal with the ones with gastrointestinal side effects. Yeah, I mean, I think obviously everyone has their own perspective and as orthopedic specialists, we've got the perspective of being interested in bones and joints and quite rightly I suppose in that we're the specialists and so hopefully we understand those tissues better than most people. I'm not an expert on pharmacovigilance. I think I've learned quite a bit in the last few months about pharmacovigilance. But clearly there are weaknesses in pharmacovigilance data. It's useful and it is a whole science in itself and adjusting for those weaknesses. I mean, it clearly is under reporting. I mean, I don't report gastrointestinal adverse events with Meloxicam who does really these days and in fact, you'll see statements now saying based on pharmacovigilance data, the rate of gastrointestinal adverse events with Meloxicam is rare. Well, that doesn't fit with our clinical experience and published work. So pharmacovigilance data can have issues and it's well known that new products have a higher rate of adverse event reporting. There was a paper out of Bristol vet school a few years ago looking at the VMD data for non-steroidal and the only variable they found that was significant for the different non-steroidal was the year of registration. So the newer non-steroidal had a lot more adverse event reporting than Meloxicam and car-per-fen which were released in the 90s because everyone's used to those and it's not news anymore. It was actually probably, you know, the newer ones perhaps had a better GI safety and that's why they were developed in that way. So you can get paradoxical effects, I suppose. The other thing to say is that of course the pharmacovigilance reporters use the VEDRA system which is the veterinary dictionary. It's a global system and it doesn't use a system of diagnoses, it uses a system of clinical signs and body systems that are affected and the reporters have to choose from a menu if you like. Now if we're seeing phenomenon that are new. for bed and vet, Mab. It's actually going to be difficult for them to correctly classify maybe. To say, I'm not an expert in pharmacovigilance, but we're not necessarily comparing apples with apples here. We're comparing the opinion of a group of specialists who clearly have concerns, and that's absolutely fine. Against pharmacovigilance reporters who have to follow a very rigid system. And the other things, things have changed as well. So I think in about 2022, the European system changed to reporting all adverse events, whereas before that, it was only serious adverse events. So for most of the lifetime of non-steroidal, it's only the serious adverse events that made it through to the database. Whereas since 2022, it's been all adverse events. So again, we're not necessarily comparing apples with apples. And human behavior has an awful lot of input into pharmacovigilance data. So interestingly for LeBrello, if you look at the adverse events that are reported by different territories, a tax year features very highly in North America. But LeBrello was licensed three or four years later in North America compared to Europe. If you look at the UK and European data early on, a tax year didn't really feature. So different territories see different adverse event reporting rates. So UK, US, Canada are all higher than countries like Italy and Spain. And also the pattern of the adverse events is different between the different territories. And there's no doubt social media these days can have an influence on things, can drive notoriety bias as it's called, where people have raised concerns about a sign and then other people say, right, yeah, I'll report that as well. And all these things have to be taken into the mix and there are ways of dealing with it. But we have to get to a point where we understand the relative risk of different adverse events. The regulators know that adverse events follow a typical curve, they rise and then they fall to a steady state. And they've of course got the data for all the other drugs. And they can compare between and they will be doing. They will be doing. I mean, in terms of, you know, evidence based medicine, where would you see the role of adverse event reporting versus a long-term placebo control trial in terms of giving us information about long term of safety of the drug? Yeah, well, sure. I mean, it's not, you know, please see the control trial, you know, high level of evidence. But it's much smaller number of subjects. And, you know, 28 million dogs receiving the liberal, you're going to see things in those data that wouldn't come out in smaller studies. So they both have a role, definitely both have a role. And, you know, and I am certainly not saying that bed and vet, ma'am, doesn't have an adverse event rate with joints, but we just don't know what that relative risk is at the moment. And I guess what I'm getting at is it seems surprising almost that, you know, the first study we have of the, you know, safety over the first two months comes out two months before a paper about, you know, long-term adverse effects and concerns me a little bit about the way that drugs are released into our profession that perhaps at least some level of long-term safety study hasn't been done before it's been given to 28 million dogs, you know, so yeah. But I also think I've been in those. I also, yeah, I absolutely agree with you in terms of that's what we probably all want to happen. But we also have to be a little bit pragmatic around veterinary medicine and the size of the market and the commercial realities. So, you know, I remember when I was back in Bristol doing my PhD, I remember the rheumatologist getting all excited because there was this new medicine to treat rheumatoid arthritis and it was an antibody monoclonal antibody against Schumannicrosis factor. That turned out to be the first ever licensed monoclonal antibody medicine. And it was licensed in 2001 back then it cost 10,000 pounds per patient per year and that is 24 years ago. We've now got antibody medicines in veterinary medicine for, you know, 50 pounds a month. And you know, that we do have to accept that is a remarkable progress in terms of R&D and science. Now, so these are the upsides but there might be downsides and if we wanted long-term studies like a decade of clinical trials in thousands of dogs, these drugs would never reach us because the cost will be prohibitive. But I guess a year in 100 dogs, it's not easy and they get me wrong. Well, it would be nice to. Yeah, the European Pivotal Field trial for a bedding vet map, dogs on there had up to nine months of treatment. But obviously, numbers are much smaller, 100 dogs. If something is a rare event, that's defined as between one and 10 dogs per 10,000 doses. So you may not see that in a trial of 100 dogs or 200 dogs or 300 dogs. So pharmacovigents definitely has a role and people are right to raise concerns. I guess what I would support is a reasoned scientific debate and as objective as we can be about the relative risks. We're all surgeons, right? I do hit replacement. It's a great operation, but it has about a 6% complication rate if you read the literature and the 10 year BVOA, hip registry data tells us that it's got a 7% mortality rate. So the dogs that died in those 10 years, 7% died because of something to do with their hip replacement. That's not something. Do you think we're essentially not being even handed between the way that we view significant adverse events between medical treatments and surgical treatments? I'd actually jump in there as well. I had a crazy case last autumn, 2012, we were all born at terrier, we should have a more clinical exam or more bloods and you know, other skinned genes, surgery, not good, could you do the surgery and eventually did the surgery? The surgery went absolutely great. Within a few days, dogs walk, we're really happy. We're like, week later started vomiting and had a ruptured stomach full, spent a month in her referrals and thankfully made it out the other side, but it was unbelievably terrifying case and really shook me after 20 years of very happily fishing out monster rodals. Like and say, with the hips with all these things, there are scary, scary outcomes sometimes. I see quite a lot of OA consults, severe OA cases and I'm very open with clients about the information and say, there are these concerns and I tell them about a tax year, polydips year and joint related events. I try and put those in perspective in terms of relative risk as far as we know at the moment, but dogs are not people and I find a lot of clients when they've got an elderly dog that's quality of life is poor. The response one often gets is yeah, but my dog can't walk, you know, so I need to do something. Now I've recently reported a suspect joint related adverse event to Zoetis. It belonged to a vet nurse and I can't explain what's happened to this joint by any other means. The dog had nearly three years of bed-invent map and I said to this nurse, well, there is a possibility this is related to the bed-invent map and her response was really interesting. She said, well, yes, she said, but my dogs had three years of less pain and she said, I've seen many dogs in our practice, she's from primary care practice that have had an extra year or two of life which they wouldn't have had before. And so she was taking a pretty philosophical view of things. You know, I think it's interesting. I always try and explain the risks to people and think that a non-stroidal is better for them in that situation than absolutely. I guess this is the problem, isn't it, with the lack of a denominator in our equation as to how many dogs are actually getting problems. That's the information we all need really, isn't it, to be able to give people good advice as to whether or not the risk benefit ratio is breadth for their particular patient. Yes. And, you know, therefore I would just say to people, if you've got suspicions of a problem, report it. That's the right thing to do. When LeBrella came onto the market, you know, I certainly as a, you know, a little bit exergent was really delighted to have another thing to help in the fight against, you know, pain. And it would be, I think, really tragic to lose it through hysteria, potentially. And it would seem there are lots of way, lots of strategies that we might be able to employ to use it in a way which gives the benefit without necessarily so much risk. And certainly for those dogs who have never had non-steroidal because they went straight onto LeBrella, you know, might it be that they can have alternate months of one and, you know, and the other and reduce the side effects of both. do we need to avoid it in certain subgrouped patients? It would seem to me that there's a lot of work that needs to be done. What would you like to see happen next in terms of research? - Well, I think, sorry guys, can you give me one second, sorry, I've got a dog going home and then first messaging me about-- - Well, your old dog just jumps up and yells and now he always looks like that. - I'm just saying that. - I don't want to be here till midnight. So what I like to see, I think what's really great is that this has really raised the profile of osteoarthritis in dogs. It was until now a Cinderella subject. A very important condition, really common in primary care practice, most specialists I would say couldn't have given two hoots about it because they're interested in surgery. But this debate has really sparked a lot of interest and actually we're gonna learn a lot about OA because clearly industry are gonna have to respond with doing more studies and they are, I believe. There are studies ongoing already. Looking at progression of OA, what is the normal progression of OA and looking at rates of where we might see adverse events? I'm encouraging biomarker studies. I can only do my bit to encourage. I'm not in academia anymore, but from this human studies, we've got some candidate biomarkers we could start looking at. So I think this is good in that we'll learn a lot more. But I agree with you Duncan, in that I think for a lot of dogs, bed and vet map has been a positive thing because it's effective and for a lot of dogs, it doesn't seem to cause a problem. And so it would be a shame to lose that tool because as you say, of amplification of concerns about joints, we didn't see that amplification around non-steroidals because Simon Lightyear, I've seen the odd dog over the years and some of mine didn't make it actually with perforated, duodenal ulcers or whatever. So you know, medics have been raising these concerns and the soft tissue surgeons because they're the ones that see those cases. And you've got this bias, depending on your discipline. And I get that, I get that. But you know, those risks have been there with non-steroidals in other ways, but we live with it because that's all we had. So I think as long as clients understand the relative risks and the more information we can give them with more data coming out, the better. And then they can make their informed decision. - That's a very interesting experience when one of my family members was in hospital, well, the real and being a typical vet, I had a good look at a chart and it was quite surprised to see that she's been given the lidabod. So you know, it's interesting how even a drug as notorious as the lidabod came to be, actually did find its way back into kind of practice. And notably, the reason I looked at that particular point was because it had finally been the one thing that had actually been effective in stopping and vomiting. So actually there can be a way back for these things if it's done in the right way, I think. - Yeah, yeah, interesting. - Well, I think that's a really good antidote to end on. Just wanna say thank you to you both for your time, John in particular. Thank you for coming along. That was absolutely fascinating to hear about your career and about the study and about osteoarthritis more broadly. Really, really interesting. So thank you very much for coming along. - Not at all. And thanks to you too for giving up your time to do this for BBOA. That's very honorable of you. Giving up your evening. So well done. - Oh, it's fun, John. - It's a good evening. - BBOA is in safe hands. That's great. - That's good. - Very good. One thing I would say is if any listeners would like to email in any thoughts or comments, that would be really interesting. You could email member@large or one word at bvoa.co.uk or you could contact their BBOA on social media. And good interesting to get some feedback on their subject matter and constructive criticism and thoughts. So any cases as well, we could pick the Duncan Brain or the guest over the next podcast. So bear that in mind, but other than that, thank you all. And good night.