Good afternoon everyone, and thank you all for joining us on this lunchtime webinar kindly sponsored by TVM UK, part of the Domes Farmer brand. So today we are reviewing the power of stem cells with Dog stem 6 months after its launch, and it's my pleasure to introduce our two speakers for the day. Almadina Padea, the chief scientific director at Erecord, who has experience in equine and small animal practise and holds both a master's in medicine, discovery and development and a PhD in pharmacology and physiology.
And Drew Tuttle, Drew graduated from Liverpool University in 2004 and spent the next 17 years in the British Army as a veterinary officer in the Royal Army Veterinary Corps. His postings included Aldershot, Cypress, Melton Mowbray, and an operational tour to Iraq. His principal role in the army was in support of military working dogs, and he has extensive experience in their procurement, training, welfare, and clinical care.
In 2022, Drew left the army to start work with Uppsala musculoskeletal clinic and continue his passion for helping animals with arthritis. When we get to our Q&A session at the end, we'll also be joined by Emma Hancock, who's one technical vet for TM UK. A few bits of housekeeping then regarding the Q&As.
If you're watching via Zoom, please pop all questions into the Q&A box, and if you're watching via the website, you can email them to office atheebinar vet.com, and we will cover as many of these as possible at the end of the session. So, without further ado, Al Medina, I think you're starting us off, so over to you.
Thank you. Thank you very much. Thank you, all the people.
I'm here to talk about the science behind the stem cells. The first, is, trying to introduce a little about, Doxton, that is the first and only licenced stem cell treatment for Caninnos treaties that has been, approved in the, United Kingdom and also in the European Union. Negative substance is a key umbilical cord mesenchymal stem cells have been proven to reduce the pain and lameness and improve the quality of life.
It is, in particular administration product with no systemic contraindication. It is formulated as a ready to use product with 7.5 million of stem cells per vial.
Thanks to the Use of equine cord stem cells is an ethical, non-invasive, and 100% animal welfare source of stem cells and have demonstrate the long-term efficacy and the qua high quality, safety and high manufacturing standards. Why we use equineumbicalcor mesenchymal stem cells, the first, reason is because we can. From a safety and efficacy perspective, stem cells are able to cross the species.
Obviously, if this, jump inies would not be a possibility, the development of this equine product in horses it has stopped. In the first stage. So the first reason is because we can, because thanks to the immuno privilege status of the stem cells, we can cross the the specific barrier with a full safety and efficacy.
Once we demonstrate the efficacy and the safety, the use, the advantage of using one of the cord were much bigger and that's why the reason we select this tissue. The first advantage is the animal welfare. For us, when we developed the product was crazy to think to make any damage to any donor just for the reason of obtaining a tissue for manufacturing a pharmaceutical product.
So we wanted to have a 100% animal welfare source of of stem cells, and that is only possible with equine umbilical cord. The other advantage is that the equine umbilical cord tissue is a very big tissue. We are talking about 1, more than 1 metre tissue, more than 1 kilogramme with a a very high number of cells per gramme.
So if we compare the equinumcur with any of tissue in the body, the number of cells that we obtain from each one is much bigger than the one that we can obtain from any other sources. That makes that the number of duplication that our cells is, are made in culture is lower than the ones needed for any other product in the market. And it is well known that the more a cell duplicating culture, the less efficacy of the product.
So, the, the equine umbilical cord mesenchymal stem cells ensure us to have the greatest efficacy in terms of duplication of the cells. Also, in terms of safety, thanks to using umbilical cord cells, only those virus that are able to cross the placenta from the mare to the fall are relevant in this problem. We don't have any problems with virus that could occur during the life because only the tissue is obtained during the birth with new phones.
So, in terms of safety, it's a more safety tissue. And also, the collection is a part of the normal breeding and ensures the sustainable and ethical source. So we can summarise that thanks to using equinum ol cord, we have a more efficacy product, more safety products, and 100% in line with animal welfare.
And a little bit about the science behind the, the product and the mechanisms of action that is the main part of my presentation and the reason I'm here today. In the Pink, orange part, we have represent how a normal urine evolves with osteritis. So the first step of the disease is once the dog make a jump, run playing with other dogs, we have a small repeated microco.
Thomas to the synovial capsule of the joint, especially the synoviocyte B of the joints. In response to this micro-repeated small homas, the synoviocyte B of the synovial capsule get activated and released to the synovial fluid high levels of inflammatory cytokines, mainly interleukin 1 and interleukin 6. In response to this activation of the synovial synoviys B.
The body sent to the joint inflammatory cells that came to the joint in a fighting mode, in an inflammatory mode. We have an infiltration of macrophagous type 1 and T cells and B cells in an inflammatory phenotype, type 1. In this inflammatory phenotype, macrophagous and T and B cells secrete inflammatory cytokines, mainly TF alpha and interleukin 6.
So in the second stage of the disease, we have an inflammatory environment in the synovial fluid and in the joint mediated by inflammatory cells, macrophorous, T cells and B cells, and inflammatory cytokines, TFfalpha and interleukin 1. In this state, with this inflammatory environment, the cartilage of the joint is damaged. As you know, the, cartilage is a very delicated tissue with a very delicated equilibrium between the anabolic and the catabolic activity.
So it is very important to try to take care of this tissue because if something is going to destroy the tissue, the recovery capacity of, of the body and the regeneration capacity of the tissue is very, very limited. Unfortunately, this inflammatory environment mediated by inflammatory cells and inflammatory c cytokines have a very negative effect in the on your stasis of the cartilage and in the extracellular matrix and increase the degradation of the tissue by the release of degradation proteins like metallorotenasis, especially metaprotenasis 13, that has a direct impact in the loss of the cartilage. Once we have lost the cartilage, the control bone of, of the dog, in response to this loss of the cartilage response by generating new bone.
And it's what we see in typical X-rays with the typical intenshytes and the new bone formation. Nowadays, we have many treatments in the market that works in a cytokine level in the cascade of the inflammation. And that's why all the treatments that we have in the market right now have to be using with quite often.
Treatments, depending on the treatments, we have treatments every day, every week, every month, but we have to be repeated in a chronic process because we only work in the cascade, phase of, of the inflammation. What we look with the stem cells is to work in the inflammatory cascade, but at, at a cellular level. And it's what we wanted to explain in the blue sides of the slide.
So once we inject the, the stem cells, these stem cells get activated by this inflammatory environment and in response to This activation, they secrete very high levels of different cytokines, mainly prosaglandin A2. These cytokines makes immunomobulation in the inflammatory cells of the joint and switch off and change the phenotype from an inflammatory. Phenotype to an antiinflammatory phenotype.
So transform the cells from an inflammatory cell to an anti-inflammatory cells. So, macrophagous type 1 change to macrophagous type 2, anti-inflammatory macrophagous and T cells and B cells change to T cells, B cells, helpers and regulators. This is the only medicine nowadays that changed the environment of the joint in a cellular level by changing the origin of the inflammation that is the cellular, the inflammatory cells.
Once the stem cells have changed the inflammatory cells to anti-inflammatory cells, these anti-inflammatory cells will secrete anti-inflammatory cytokines and growth factors to the synovial fluid. These anti-inflammatory cytokines and growth factors have two effects directing the joint. In one hand, typical anti-inflammatory effect that we know, less pain, less lameness, less effusion, and in the other hand, makes a protection and regenerative environment in the.
That makes that the body is able to restore the normal function of the stem of, of the cells. So what the stem cells do is to create the ideal environment, but is the own body of the receptor, the one who has to regenerate the tissue. So considering this is important to take into account the age and the state of the disease if we are looking for a regenerative action of the stem cells because it's not the stem cells per se, the one who is going to differentiate and to replace the cartilage that, that has been lost during the osteoarthritis.
The will create the ideal environment that will be their own dog with their own cells, the one who has to make that regeneration. So it is important to take this into account when we select the case for the treatment with the stem cells. Essentially, if we are looking for a regenerative properties of the stem cells.
So we can summarise that doxte is a 3 in one medicine. In one hand, has a unique immunomodulatory effect. It's the only product in the market right now that is able to change the environment from an inflammatory environment to an anti-inflammatory environment.
On the other hand, is an anti-inflammatory drug. Thanks to the secretion of anti-inflammatory cytokines and growth factors, we will see an immediate anti-inflammatory effect in our patients, less pain, less lameness, effusion, all the Typical signs of inflammation and in the other hand, has a a potential tissue regenerative properties thanks to the environment that they create and the potential of a slow down the progression of the disease. As I'm sure you imagine for obtaining a European and UK marketing authorization, the amount of evidence that we need to demonstrate and to submit to the authorities was very big, more in a very innovative product as Doc was, and the first one in the market, European.
And also worldwide. The doxin is the first product for stem cells along the wall. So the amount of evidence that we need to submit obviously was much higher.
We conduct one safety study in 8 dogs, treatment, placebo and studying the stem cells, with 3 arms, arms. Then we conduct as exploratory study just in 25 pilot dos. And then we conduct the pivotal or confirmatory study with a higher number of patients.
All these data were submitted to the authorities for the approval of the product. The pivotal study has been published in JACMA. It is an open label, paper, and you have the, the link if you wanted to have access, direct access.
And it was designed as a multicentric, randomised, blind, and controlled clinical trial. And one of the most important thing of this study is that for the first time, we use plate force as a tool for the registration of a medicine with regulatory purposes. When we were investigating all the different clinical trials of all our competitors in the market to get ideas for the design, it was surprising that even the last product that has been released in the market a few years ago, even those new products only use surveys from owners.
As a primary endpoint. For us, the use of owner surveys is very valuable because obviously, the owners have information that is difficult to assess in a 2 minute clinic. But, for us, the owner is important but should not be the case.
Point of the efficacy of the product. So, apart from the owners that also were surveyed for this study, we decide to use a plate force as primary endpoint because we wanted to have a 100% objective. Measure.
And this is another innovation of Doxton because Doxton is the first product that uses a 100% tool for obtaining the registration of, of the product in the European Union and UK. In terms of results, as we said, we use the plate force as primary endpoint, and we select the 5% of improvement in the peak vertical force that is considered the gold standard for obtaining a clinical relevant improvement. And we see that 63% of our dogs improve more than 5% of big vertical forces in the plate fors compared to only 8% in the placebo group.
This very low placebo. Shows us that the tool that we select, it is very, very objective, and only those animals with a real improvement thanks to the medicine will reach the 5% increase in the peak vertical forest. Maybe you think that 63% is not so much.
Maybe you think, well, it's almost half, half. We have to put this data in context because, you know, that osteoarthritis is a complex disease and that we have to read this this disease as a multimodal process. In this clinical While all the other multi-mobile approaches were forbidden.
It was not allowed to use any other treatments. It was not allowed to make physiotherapy. It was not allowed to change the weight of the dog.
The only things that we could make is to put do them. All the other arms of the multimodal approach were forbidden. That makes that when we use dox them inside the conventional multimodal approach of the treaties.
The results of, of this product are much higher and are the results that we are finding right now in our, after 6 months of launching of Doxstem, we are seeing that the real practise evidence of efficacy of the product is around 90%. Also, by putting it in con in context, as we said, There are still many things that have data of improvement in plate first because Doxton was the first one who used this endpoint from a regulatory perspective, but in the biliography, we could find data on the use of meloxicam or carprofen that are there to treatment. That we use conventionally in our practise, and we see that the efficacy in do with dox them in the plates is higher than the one reported by meloxicam or Calprofen.
So we can ensure that doxte efficacy is higher than our conventional treatments. Regarding safety, this, study has been also published recently in Frontiers. It is also an open, paper, so you can find it in, in the link attached, and then you can read it if you have interest, as a summarised.
We have never seen any systemic adverse event ever, neither any severe adverse event that makes suitable or even ideal for dogs with other concomitant pathologies that may, maybe make dangerous to use maybe anti-inflammatory drugs or other treatments, conventional treatments. So, that makes it suitable for these kind of drugs. We have seen 100% safety in the repeated administration and you can have all the data about the immunologic safety of equine cells in dogs in the, in the publication of, of Frontiers about the humeral and the the response that we, that we were tested in this safety study.
And We have seen a 10% of increase of pain and lameness 24 hours after Doxam administration. This inflammation was also seen in some dogs of the placebo group. So something of this inflammation is due to the administration process.
Inarticular administration, sometimes it's a bit painful. So we recommend you to use one single dose of anti-inflammatory drug the day of doxte administration to try to prevent this transitory increase of pain and lameness due to the infiltration process. And just for end my presentation, I always try to end with this slide because when, when I make all my, my lecture, this is a question that is done always.
And it's like, OK, thanks for everything, very clear, but what would be the ideal patient for STEM folks? And the reality is that Years ago, we thought that the stem cells is was ideal for dogs where nothing else works. We treat with all the treatments in the market, and when nothing else works, we move to a stem cells.
And that's the, the, the state of, of heart right now. People usually see the stem cells as the last term. And my objective here with these lectures, with explaining the mechanism of action is to try to change that, that mind and not see the stem cells just as a last treatment and see the stem cells also as a first line treatment in young and adult dogs.
So returning to the question, which is the ideal patient, the first response would be Old. In our clinical trial, we accept dogs from one year old to the end of the life. We accept dogs with mild strategic changes, but also with severe.
So we accept all kinds of dogs and the results in terms of efficacy and safety that we were presenting here were with all types of cases. But it is true that depending on the severity and the age of the dog, the results would be different in terms, especially in terms of regeneration. If we are looking for a regeneration capacity of the stem cells, we have definitely to move to young and adult dogs with mild to moderate changes.
If we use the stem cells in senior dogs, we will obtain a very long-term clinical clinical efficacy. We will increase the quality of life, and we will ensure the good being of the dog, but the regenerative properties of the stem cells would be negligible. If if apart from those senior and very advantage diseaseed dogs.
Where we can have very good results. If apart from that, we also move the stem cells to early states, apart from long-term efficacy results, improvement of the quality of life, we will also create a regenerative environment that could slow down the progression of the disease and trying to prevent the evolution to a, a very advanced stage of the disease. So you can use Doste in any state, but for the regenerative properties, it's important to take into account the severity and the age of the dog.
And don't see the stem cells as a last chance treatment because in reality, it's the opposite. Stem cells should be seen as a first-line treatment for early diseases dogs, and we will try to prevent the evolution of the, of the disease. Thank you very much and the future is here.
Mm. Right, Thank you, Elena. That's, that's quite a tough act to follow.
So, thank you for, thank you for the high science on that and the, and the background on, on, on dog stem. My, my brief here today is to provide a, a sort of a clinician's guide, the practicalities of using stem cells in, in regular practise. And there's a, there's a couple of common themes that you'll pick up on as we go through.
. I'm gonna go over this relatively quickly because I think I'm, I'm hopeful that there's there's some good questions at the end. So, backing straight on, . Disclosures.
I'd just like to, to point out at this stage that, I have no, I have no disclosures to make. I have no affiliations to TBM Equicord, or, or Domes Farmers. So, NUSA, I work for the NUPSala MSK clinic, and we are a, a niche, musculoskeletal clinic, using objective gait analysis for the management, of, canine arthritis.
And the dog stem has proven to be, one of the tools that we've, that we, we're relying on. The objectives today, Ahmadonna touched on the, on some aspects of arthritis and the, and the kind of the pathophysiology, but I'd, I'd like to just kind of remind people about the, the temporal, . Kind of set up for arthritis and when we should be looking, a little bit about case selection, what to look for, what's, what's a good case to use this on, and what's not.
I, I do quite a lot of my consults spent, de-educating owners, about what stem cells are, and also what they, what they might bring to the party. So just how I kind of manage that with, with my, with my clientele. A little bit on injection considerations, what we do, in terms of the practicality of administration and a quick case study, because, everyone loves a case study.
And then, I'd like to touch a little bit on critical thinking about maybe my journey towards, the adoption and integration of intra-articular therapy into, into my, into my practise, and where, mesenchymal stem cells sit in, in OA management. So, Osteoarthritis, we've all seen the pictures, we've all seen the X-rays, it's the big cauliflower hips, it's the ununited anineal processes, it's the, it's, you just look at them and go, ouch. But the reality is that arthritis, if we grade it on, on a 1 to 5 basis, we know it starts in the synovium, we know it starts with inflammation, we know it progresses through stage 2, where we're starting to get mild clinical signs and we get some cartilage involvement.
The significant thing to note here is that you can get to grade 3 without really any obvious signs on, on radiographs. And both of the images on the left hand side of the screen are arthritic dogs. They've been through this clinic.
All of the, all of the radiographs taken today have been through, patients in the clinic, taken with the owner's permission. And the the thing that I would just like to highlight there is that. If you have pain, if you have suspicion, if you have swelling, if you have the clinical signs of arthritis, and you take the X-ray and it looks like the one at the top, you, you just, you simply cannot rule arthritis off the differential list.
It's, it's entirely possible and even plausible, that arthritis is sitting there right as, as your number one differential. So, that's a little bit about the, the stages, and I'll, and I'll touch on that when we come to case selection, now. So, in terms of what makes a good candidate for stem cell therapy, well, the first thing is you, you've got to confirm your diagnosis.
It is, that we all know, the, the, the adage of, of animals don't walk on their images. You really need to be sure, through clinical history, clinical examination, really careful clinical examination, the localization of pain. Through imaging, whether that's plain radiography or advanced imaging, but make sure that what you're actually dealing with is, is your primary problem.
You can stick any amount of intra-articular therapy into a joint you want, and it, and it won't work if it's actually the, the proximal tendonitis that's actually causing the dog pain. So just be sure that, that's the, you've, you've got a confirmed diagnosis. No particular reason, these have all started with C's.
I don't know how that happened, but, next thing is comorbidities. So, again, we see within the clinic here we've seen, our age range has gone from about 12 months old to 13, maybe even 14 years old. Probably the most significant thing about, about your ability to administer intra-articular therapies is the anaesthetic, safety and stability of your patient.
So, can you get it asleep? Can you get it still? And equally, do think about the long game here, whatever, whatever your, your approach is to intra-articular therapy.
If, if the dog's got, stage 4, stage 5 arthritis, which is causing it pain, but it's also got a rampant heart disease or renal disease in end stage. It, it is, it is entirely plausible that that one of those comorbidities is, is going to, affect the animal and affect its welfare and quality of life more so, than the, than the arthritis. So, just be careful, make sure you make a considered decision about, about using it.
Contrary indications, there are really very few. The, obviously, if you've done radiography or if you've done, If you've done, imaging of some form, then you should be able to rule out neoplasia. Sepsis, there's, it's always a tricky one is, we, we keep getting told, you know, just rule out, infectious, .
Infectious causes of, of arthritis. And, and to date in dogs, I've seen innumerable numbers of dogs with pain, swelling, effusion, reduced range of motion, crepitus, and, and, and sepsis never crossed my mind. It's one of those things that you, if it, if you have an old dog with multiple, sites of pain.
It is highly unlikely to be sepsis, but just make sure you have considered it and ruled it out either physically or through, or through your sort of your, your patient selection. Dermatitis is an interesting one. So if you are going to enter the joint cavity, just make sure that there isn't some kind of active infectious dermatitis that you're gonna be tracking your needle through.
So that would be probably one of the more likely, reasons for, for not proceeding, at least until that dermatitis is under control. And then things like fractures and instability. Again, no amount of stem cell therapy, or, or, or intra-articular therapy is going to fix an unstable or, or, or clinically, .
Yeah, unstable, joints. So, for example, a, a case, excuse me, a case in point there would be, a, the, the full ruptured cruise ships. If there is instability there, then there will be pain and there will be, continuing arthritis.
So, Things like intra-articular therapies will aid in that, but they won't fix them. So just make sure that you've, you've, you've taken that into account. And then complicating factors, it is rare that cases will come in with a single joint.
So just be mindful, particularly, we, we are very fortunate in having the gait analysis, treadmill that we can really analyse and look for compensatory gaits. So whether it's chronic disease and chronic offloading of a, an affected limb. The, the compensatory loading on either the contralateral or the ipsilateral limb may also be problematic.
So take a holistic view about your lame mismanagement. In terms of owner education, I, I do have to tell them what it is not. It, it is not little ninja robots, for some reason which I can't quite fathom.
The stem cells have also become synonymous in a lot of, owner's mind with, with genetic engineering, and, and, and these are not genetically modified super soldiers going in and, and taking out a pre-programmed target. So I do have to sort of, sort of, unlearn, some of the clients in, in terms, and this is just a useful, this is a useful analogy. I use a lot of analogies, I think they're great.
But this is a useful one that I use, when it comes to stem cell therapy. And we were talking there previously about this idea of, of balance and, within a healthy joint, there should be, both, both growth and destruction. And that is what is going on in the left hand, the top left of the screen here.
I, I describe the joint as being like a, a building site where there is order, there is structure, there is, there are, there are, instructions being given about what should be destroyed and what should be built. And as you move into the top right of the screen, arthritis takes over, and those negative anti-inflammatory aspects start to, to take control, and they, they cause more destruction, and the, the regeneration and the growth, just, just slows down or stops altogether. And so you get in this, this kind of imbalance going on.
Again, the stem cells, what it is they're doing, is sometimes, the owners can't quite understand. And, and it is not that they are going in there and patching things up and doing things. It is that, it is that influence effect that they're having and that, that immuno immunomodulatory effect they're having.
So, within the same analogy, I described the stem cells as being like a, a, a contracted problem solving site form and. They're coming in and they're just giving directions to, to the, the building site, to the joint, you know, what should we start, what should, what should be regulated. They're also, you know, responsible for finding the raw materials, getting them to site, getting the, getting the right people to the right place at the right time.
And the, and the effect then is, is the reordering of that building site and a, and a joint that is now calm and happy and healthy. So in terms of injections, considerations, skin preparation, I talked already about the, the dermatitis, do, do watch out for that one. But the skin preparation is, is absolutely as you would do for any normal aseptic procedure.
I do, when I, when I speak to vets who are considering using intra-articular therapies, they, they, they, a, a common theme is this idea of introducing infection and the risk of sepsis post-injection. And, and there's a couple of interesting points there. The first is that, there is no, there is no significant difference between, injecting a joint and performing either abdominal or thorachocentesis.
Yet those latter two procedures are things that we're all entirely comfortable with practising in, in the normal clinic environment, but for some reason, the, the joint has become. It, it, it just raises these worries in people about, about the idea of, of, of injecting into it. And, and an interesting study, it's only a couple of years old, but they actually looked at the, the difference between clipping and not clipping, but still surgically preparing the area.
And they found that in clean, short-haired dogs, there was no difference in bacterial colony forming units if the dog was clipped or not clipped. Now. Within that paper, the caveat is that there's a lot more work to be done to see if that is something that we should use to change our practises.
I will not be leaving dogs unshaven, at this stage. But what we can deduce from that is that the, the, the proper sterile preparation of the skin is, is, is enough. Some people drape, I personally don't, I find that it just interferes with my sort of 3D appreciation of the anatomy, of trying to get into the joints.
Once your dog is on the table or your patient's on the table and they're ready to proceed, then we get the, the stem cells, out of the fridge. . Stem cells will arrive cold chain, it's worth as a top tip.
It's worth letting somebody know, in the practise that they are due in, so that they can be, they can be expected, and when they come in, that they are definitely, they do definitely go, into a, into a fridge within the practise and maintain that coal chain until they're required. Once the dog's ready, then we just bring them out about sort of 10 minutes or so beforehand to bring them up to room temperature. And then just prior to administration, we'll, we'll kind of warm them up, to as near to body temperature.
That's just, just by holding the syringe in my hands before, before, in, injection. In terms of equipment, it's the most beautifully simple procedure you'll ever need, or you'll ever do. One, I, I use 21 gauge needles, because I'm, I'm comfortable with that.
And a 2.5 mil for, aspiration and a, a 2.5 mil for injection, and, and that is pretty much it.
Once you've, once you've got into the joint aspiration, just, just withdrawing, to make sure that you are in the right place. And if we think about the arthritic joint and that synovial fluid, it's, it's like a, a, a, a nasty cytokine soup. So actually aspirating a lot of, particularly if there's a fusion, aspirating that, that effusion, getting rid of it, getting it out of there will actually help, and, to, to, before you, before you put the stem cells in.
There is some, I don't use ultrasound, apart from, increasingly in hips, particularly for, for sort of overweight dogs. There's a paper down there, which is, which is a very neat, elegant little paper where the procedure for ultrasound guided injection into hips is, is, is relatively simple, but for all other, it's, it should be, surface anatomy should be, should be ample. It was mentioned there previously about aftercare and flare management.
I rest the dogs for a couple of days, 2 to 3 days post injection, and it is entirely possible to have a, a, a transient sinusitis following, injection. And, and that, when I described that to our owners, that's, that's just a, that's the physical reactivity of a needle being put into an already angry, angry area. If we do see, transient synoviti, then we, we tend to just manage it with the doone analgesics, potentially just rest and, and the application of cold packs.
That, that can help, but it's, it will normally be, if, if it does happen at all, and it, it happens relatively uncommonly, it should be gone within sort of 24 hours. Analgesia, so Doxstem is licenced for the single administration of a non-steroid or around the time of injection. I find that the majority of the cases that I see are already well into their arthritis journey, and, and are already on multimodal analgesia.
Interestingly, in human medicine, they don't, give, anti-inflammatory specifically NSAIDs around the time of orthobiologic, administration. But you can tell people to rest, and you can tell people to stay off their legs and, and, and rest up to the time of their procedure, and that, that just doesn't happen in animals. So from a welfare perspective, I maintain their analgesia throughout.
And certainly speaking to my peers, working in this sort of field, everybody does, it, it, I think the, the welfare detriment, is, is, would be excessive. And just a quick touch on increasingly practises using laser therapy, . We, we use it immediately prior to administration.
So a quick case study, this, this poor chap has had, has really been in the wars, he's only, he's not even 5 years old yet. A, a total hip replacement at 11 month old with a revision that failed and ended up with a femoral head and neck excision. The other side was never treated, and you can see it's, it's just a disaster area there.
And then to top that all off, he was, he was diagnosed in 2019 with bilateral humeral intercondylar fissures, was treated with transcondylar screws, but then didn't really receive any follow-up due to, due to COVID. So, this is, this is, I think we can all agree, a grade 5, grade 5 case. And when we look at his, his gait analysis, we can see it was his right for that was, that was the worst affected.
Interestingly, the lowest, pressure was on his right hind, which is actually the leg that had the femoral head and neck excision. But you can see him on the treadmill there, he's just extremely, extremely. Stiff and hesitant, and even though he's going incredibly slowly, he's actually in a, what is classed as a trot.
It's a two beat gait, and the reason he's doing that is to maintain his stability because he's just laying uncomfortable. So when should we be using this? I, I, I, we touched on it earlier and again, and, and I bring up the, I bring up Iris because we all accept and, and agree with Iris, and if an animal is tested for, for chronic kidney disease, then even if it hits grade one, we treat, we make lifestyle modifications.
And, and in many cases, that, that is the same with arthritis that we talk about the, about the sort of the adjunctive, lifestyle changes that need to happen. But these are, these are all cases, again, all these X-rays are taken, and if we, all of these cases would be amenable to, to stem cell therapy. They're all confirmed to be located within the joint.
They've all got pain, they've all got a fusion, and they grade from 11 to, sort of about a 4 and then a 5 at the bottom there. So, you know, I, I just challenge people who say that, you know, that we should be maintaining our intra-articulars until the end. We don't accept within other disease processes to, to leave it to the last stage to, to treat.
So why do we do it with arthritis? And this comes a little bit about what I was saying about critical thinking. The use of intra-articular therapies is really not widespread within companion animal medicine.
There are people doing it. And, and a lot of the, a lot of the, arguments based around cynicism, it's just a, it's not gonna work, so we're, we're not gonna do it. And I, I was minded of that, of that quote, insanity is doing the same thing over and over again and expecting different results.
Yeah, if we just keep doing the, the same bog standard procedure of systemic anti-inflammatories and some lifestyle changes and wait till it's sort of really late and then, and then refer for advanced imaging, then nothing will ever change. But just to show critical thinking, I looked this, I looked this very expression up. And whilst I was absolutely sure I was attributed to Arthur Einenstein, there was no record of him ever having said it.
So be critical, think about what it is, you know, if you have concerns about, about introduction of sepsis, look at the literature, there's a tonne out there, that says that this is a, this is a really good, worthwhile approach. Where does it fit within management? Well, it fits with all the other stuff.
On the, on the top left hand side, weight management. You know, the, the studies are there, just 6% weight loss, in, in an obese animal will have a significant improvement in their, in their comfort. Dietary management, the use of, and that includes the use of, .
Sup supplements and things like that, exercise modification, the use of, of, of systemic medication, and then there's, there's always that nuclear option of surgery and it fits within all these. The, the use of, intra-articular biologics does not take away from any of these. All still may be required, and, and actually will be required.
So, what happened with, with Buddy, well, this was him taking just 4 weeks post surgery. I'm just gonna let them, talk through . What happened with him.
This was following injection of stem cells into both elbows and into his, his non-operated hip. As you can see, Drew. There's happiness.
Has not diminished in any way. Hey buddy, but he's . Out of scale of mobility.
He's amazing. A lot more comfortable. He's now getting back to his general run, trying to get back to his runabout.
We're managing them very well, not running on concrete. But he's getting to have a little play on the grass and on ploughed fields and everything, but. From what he was walking To what he is now, this is the best he's been like for a very long time.
Good. All we can say is thank you very much. So, that concludes the end of my presentation.
I'd just like to take a couple of, a couple of take-home points. It's, it's, stem cell therapy is not a cure. There is no cure for arthritis.
And it is likely that whilst it fits in with, lifestyle management and all those adjuncts that they are talked about, it is likely that, that some form of follow-up. So do, do follow these cases, get them back in. It's not a inject and then.
You know, wait until the Lena comes back, you need to be more proactive than that. Be rational in your case selection. You saw the difference in body in just 4 weeks.
Just imagine how much more effective stem cell therapy would have been if, if that had been done prior to his elbows, looking the way they do. So, so think. Early, think, intervene early.
If you do, if you do administer when it is like that, then, then just consider it to yourself that it is it a fair test. It, it, it is, it, it's a pretty tough, Buddy's case was a pretty tough one. Be a critical thinker, as well.
Do think about your concerns about intra-articular therapy and the use of stem cell therapy, and, and just question yourself as to whether your concerns are based on, on science and evidence. And then, just on the right-hand side here, the, the, we are, strongly affiliated within the clinic with the Veterinary Osteoarthritis Alliance. So, they're fantastic resource, dedicated towards the, the education and management of, of osteoarthritis.
And that concludes. Thank you. Thank you so much, Drew and Amadina, of course, for the earliest section.
So we've now got to the, the question and answer area of our, of our webinar. So there's a few that have come through already, which we're gonna work through now, but if you have got any driving questions that haven't already been answered, now is your opportunity to pop them in that little Q&A box at the bottom. So let's start with this first one, from Sebastian.
He says, are there any data regarding the use of dog stone after an arthroscopic surgery, for example, FPC in the elbow? If yes, can you give an advice on which day after surgery one can use the product? Who's taking that one.
You're lucky, you're lucky hesitant. I, I, I know what the answer will be is, is, is that there's gonna be no, there's, it's not gonna be any studies regarding the use, post-surgery. And, and Emma is nodding sagely, I can see that.
The, I think the, the, the question is that. The issue with, with a lot of this, the use of, of technologies like this, is that where there is, there is currently insufficient evidence, that does not mean that evidence is being gathered on the way. And certainly I have a strong interest in the mains or in the .
In the, in the monitoring and maintenance of post-surgical cases, because just because the surgery has been completed, and just because the joint is now is mechanically stable, does not necessarily mean it's physiologically stable. So I think there is a case to be made, purely by deduction and by consideration of evidence. But it, it would need to be clear that that would be a, that would be an off licence use.
In terms of timing. The, the product is licenced for intra-articular, so, it needs to go where you put it. So if you have, if there has been a breach to the joint capsule, then it seems, it seems prudent, to wait until, until that, that integrity is back.
So, so administration at time of follow-up x-rays or things like that would be. But maybe, maybe be useful, rather than going at time for surgery. Would you like to, would you like to, I wholeheartedly agree with what you've said, in that we would never say.
You know, dog stem or any stem cell preparation is going to be in replacement of a surgery. So if you are going to do that surgery in the first place, do that surgery. But, for example, like Drew said, yes, you may have done that surgery, but we know that there's a potential for arthritic change to be happening and to continue and that destructive process to continue.
So there is a place for its use afterwards. Like you said, if you're doing a surgical procedure, you want, and we want to put in stem cells, we want a joint capsule that is intact. So we say to wait at least 2 weeks.
But if you are doing, a post-op x-rays a few weeks down the line, then that's, that's a most appropriate time to put them in. Brilliant. Thank you.
In, in fact, for, for my, my point, in the clinical trial, we accept dogs that were in surgery at least 12 months before the treatment. So it was not excluded, the fact that surgery was done before. But It has to, to last at least 12 months.
Makes sense. Brilliant, thank you for that. Wonderful.
OK, you've kind of answered this next one, but I'm just gonna clarify it. I know you obviously you, you had in your, injection procedure slide, Drew, you kind of covered it off and what we've just been talking about is the licencing is for it to be used into the joints. But is there any circumstances where you would use it in any other methods such as IV?
That's what the, the question being asked, Would you use it in any other formats? I, I, I, I, I mean you're gonna, you're gonna pick that up from a, from a clinician's perspective, I'll, I'm gonna then you, you go for it. Well, from, from a scientific perspective, the product, has been obviously licenced for indicular use, but could be used intravenously because it's safe and in fact, we are now conducting and developing the new product from, from us that would be for intestinal global disease.
And in this product, the application would be intravenous from, so from perspective, the XTPN and the cells could be used intravenously. The point is that the mechanism of action would be different. All the environment that we have seen in the slide that the stem cells create where are, when are injected intra-articularly will not occur when we inject intravenously.
We will have an anti-inflammatory effect globally when we have osteoarthritis and Pain in the, we also have pain in the, around the around the tissues. So we will probably have pain in muscles, we will probably have pain in tendon, in ligaments, and in the intravenous administration, we could work in that systemic inflammation, but all the magic and all the, all the Change of the environment that the stem cells do when we inject it in particular will not cure if we inject it intravenously because the amount of cells that are able to cross the capsule, the joint capsule to go inside the joint, potentially will not be enough to make all this magic. So, yes, could be used.
Yes, probably. Probably you will see effects because when we have a osteitis, we also have involvement and pain in soft tissues in surrounding tissues of the joint and the cells will act in that tissues, but all these environment changes and the regenerative properties and all that magic will not occur in the intravenous administration. Brilliant.
I'm just gonna say, I'm just gonna say from a regulatory point of view that don't forget that dog stem is licenced for intra-articular injections and not intravenous injections. So if you are ever looking to do that, then you do need to think about Cascade, getting owner's consent, anything like that, and just thinking about the limitations, as Alma Dena said. Brilliant.
Thank you. OK. And, I mean, we saw, as you shared, Drew, the wonderful video of, of Buddy there, and you said that was 4 weeks after, after treatment.
Somebody has commented, how long does it take to see positive improvement from just observation? So, is that 4 weeks, is that kind of standard, or could you see some improvement sooner than that? Or, on average, what you, what were you kind of looking?
I, I think it will. I think the the variability on that would be massive, buddy, . Buddy's situation was, was quite extreme, and, and in his case, was literally the last ditch attempt, because everything else had been tried.
He was in, he was at the point when he came to me where he was on subcutaneous ketamine on a regular basis to try and manage his pain. So, so his, his case of about 4 weeks kind of chimes with. The, with the, with the sort of reported outcomes, the, the licence or the, the data sheet suggests that it might take 6 to 8 weeks, but more likely to be over 3 months.
And then, it, it's sort of. Unfortunately, Buddy was supposed to be here on Monday, for his review, but the car broke down, so I didn't manage to get the, to get the, the, the, the gate analysis data in time for the, for, for the presentation, but I think it, it will be it. If the dog, if the principal reason for the dog's pain is inflammation, then, then you, you, it is entirely reasonable to, to say that you'll see it within 4 weeks.
I, I, I stress to owners that don't expect anything tomorrow. And I suggest to them that they get weekly videos because in the same way that you watch a plant grow, you can't see those little changes. So actually, if they, they video them on a regular basis, they'll actually be able to track those improvements.
So it's, yeah, sorry, long, long answer to a pretty short question. It depends. That's a perfect answer.
That's what we needed to know, so thank you for that. Now we're, we're really short of time, but I'm gonna see if I can run through just a few. Hopefully quick ones for us.
We've got one, would this be a good option for a partial CCL? Emma, Emma's looking at me, Emma's looking at me, . So.
I'll just see what you say first and then closed mouths, gather no feet, as they say. Right. Partial, so it's a really interesting one and it's an area that I'm, I'm trying to actively tracking at the moment.
There is a, there is some work, there is some work being done using alternative orthobiologics for partial cruciates where . Following confirmation via arthroscopy, that's important to note in this case. They're following, following confirmation by arthroscopy and with follow-up arthroscopy, which doesn't happen in the UK so you can establish from that that it was done, elsewhere.
. That they used, they used an orthobilogic to, I think it was 2 or 3 administrations. And it did on follow up cause, some degree of repair to the cruciate ligaments, and in some cases, that, that led to resolution. Some of those cases were still required to go on.
There is no, currently no evidence, and, with the use of stem cell therapy that I am aware of for the use in, in partial cruciates. But if we just think about what is happening from a pathophysiological perspective, it is a degradative inflammatory process that leads to the rupture. So if you can apply a regenerative.
Approach, then in theory, it should work. But it, that would be, that would both be off licence and, and it would be, so the use of, of, stem cell therapy in that, that case would be off licence, but it would also be by extrapolation from, from other orthobiologics. So the theory is, is there.
But I would say that it's, that tread carefully, in terms of, in terms of application. I'm happy with that. And we're like the police sitting there going, yeah, we'll we'll accept that answer.
I mean, there's a similar one here. I, I would say it's related, you know, would you combine the stem cell products with a PRP . I'm Dana, do you wanna weigh in?
Well, maybe you're, you're, me as, as a developer, we have demonstrate safety and efficacy only using Doc, and I am not developer of PRP. So I have no my own data. I know that from a practical perspective, sometimes, PRP and, and Stem cells are combined and it could be seeing good results, but from a developer perspective, I think that I cannot give too much valuable response.
I just wanna try and catch, catch on to that and just give a little bit more information, . It is specifically stated for dog stem, unfortunately, that you can't use any other intra-articular, product at the same time as dog stem. So, again, it's, it's would be classed as off licence to do that.
I appreciate that there is clinicians out there doing different stem cell therapies alongside PRP. And there is also publications to, to kind of look at the efficacy of these. So again, it would be an extrapolation of those.
The only thing I would say about PRP as well is that, it can differ in its quality when it's made. So some Some processes to make PRP seem to be much, much better than others. And what you don't want to do is potentially put a subqual PRP in with dog stem, and you may actually just counteract the effects.
So, I again, I would say like the previous question, use caution and off licence. Brilliant, thank you. We, we, there's so many questions coming through now, and we're not gonna have time to go through them all, unfortunately, but I'll, I'll just finish on this one because I think it's a, it's a nice one to close on, which is how, how long would you expect the changes to last, before you need to re-inject, you know, to reapply dog stem.
Do you want to pick up on that, Amaam? Yes, well, I, I can tell about from a regulatory perspective, what we have seen in our clinical trials, we have a long-term, 18 months long-term clinical trial, and we saw that 60% of the owners reported more than 6 months of efficacy with one single application. And from those 37 reports.
More than 12 months. Considering that we only accept the change of the samples was not a multimodal approach and that the cases that we received in the clinical trial were mainly very severe cases. So these figures in real practise with the multimodal approach and with dogs that are not And the, at the end of the life and with very severe changes, just can improve.
And the evidence that we have from the real practise is that the efficacy of the, of doxin obviously depends on the case as anything, but we move more in a operation of the effect between 1 and 18 months rather than lower. I just adding that the, the, just again, think holistically, and, and I kind of approach, I, I, I adopt a make hay while the sun shines approach. So, within the licencing arm I don I mentioned that, that all of those adjunctive things, sort of physiotherapy, exercise management things, none of those could be done as part of the, the, as part of the trial, so.
The, the, the practicalities of use is that if you start seeing more comfort, then that is the time to really expedite things like adjunctive therapy, so physio, get the weight off whilst the dog's more mobile, more comfortable. Get it more active, work on those passive range of motion exercises with the physio, do hydrotherapy, do all those things, because they will all help. And then the way that we, we manage it is we, we look at our cases at 136, and 12 months.
And if we get to 6 months and everything's happy, we'll push it out to 12 months and make the decision. If we're sort of, not quite sure, we'll see them again at 9 months or sooner if required, with a view to, secondary therapy. Brilliant.
That makes sense. Wonderful. Well, thank you very much for answering all those questions.
As I say, apologies, we've not had time to get around all the questions that have been asked. There's lots still, still coming in. So I think, you know, this is obviously the, the 6 month review.
I think we're gonna have to have you back again in another 6 months and do a 12 month review, because there's still so much conversation going on, but everybody's really, really grateful, really enjoyed the session. So all that's left to say now is a huge thank you to Rebecca and Theo here at the webinar vet for making sure everything ran so smoothly today. Thank you to TVM UK for sponsoring the session and for Emma specifically for joining us on the panel.
A huge thanks, Emma. A huge thank you to Aldina and Drew, obviously for educating us on how to use, when to use dog stem for the maximum results. Such a fantastic product.
And, of course, thank you to you guys for joining us. It simply wouldn't be the same without you. I hope you all enjoyed it as much as I have, and we've learned lots, and we will see you soon on another webinar.
Thank you.
