Chronic Pain Chronicles with Dr Karmy
Join Dr. Grigory Karmy M.D., a distinguished chronic pain management physician with over 20 years of experience, on a captivating journey through the world of pain relief in his podcast series. Delving into the latest regenerative medical treatments like PRP, stem cell injections, and prolozone therapy, alongside educational discussions on pain transmission and various medical options, Dr. Karmy shares invaluable insights and real-life stories, empowering listeners to find relief and regain control over their chronic pain.
Chronic Pain Chronicles with Dr Karmy
Episode 12: Regenerative Medicine from Biotech Industry Perspective
Send us a text with your thoughts on this episode!
Join Dr. Karmy for an in-depth interview with Dr. Jennifer Woodell-May who was instrumental in the development of the newest treatment for osteoarthritis.
In this episode, Dr. Woodell-May answers the following questions:
1. How are new autologous and regenerative treatments created?
2. What are some of the obstacles to creating new autologous, cell-based therapies?
3. What does the future hold for this field as seen from the perspective of biotechnology industry insiders?
Tune in to this podcast episode to find out!
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And in the mid 2000s, I was working with a surgeon who was asking about a specific cytokine called IL 1RA, Interleukin 1 receptor antagonist, and asked, Hey, how much of that is in your PRP? And we did a analysis to look for it and there wasn't much. And so I was like, okay, that's interesting. So we started a path to try to find it within the blood, and then how could we concentrate it to make something that was more an anti inflammatory cytokine as opposed to a growth factor, which is soup, which is what a PRP is. And in doing research, we discovered that the major anti inflammatory cytokines in our body are actually produced by white blood cells and not platelets.
Dr Karmy:Hello, this is Dr. Karmy for Chronic Pain Chronicles, and today we have the privilege of having Dr. Jennifer Woodell-May, who was one of the scientists, or perhaps the main scientist, I'm not sure, involved in development of a new regenerative medicine approach to osteoarthritis, nSTRIDE, and, I believe a number of other regenerative medicine approaches. You can certainly correct me to talk to us today about where the field is now and hopefully where it's going in the future. Hello, Dr. Woodell.
Dr Jennifer Woodell:Hi, thank you for that introduction.
Dr Karmy:I was, looking at your LinkedIn profile a while ago. And I'm dating myself a little bit. I am about at least 10 years older than you. And What struck me was that you went straight into industry. At least when I was in medical school, I dabbled a little bit in research. And the standard path was that you go from your PhD to a postdoctoral fellowship. Hopefully your PhD supervisor managed to land somebody good and prestigious. And then you try to become a professor at the university. Yes, biotechs existed, but that is not what most graduate students aspire to. It was more of forced landing if you don't get a professorship at a prestigious university, or maybe you only went as far as master's and never went to a PhD. You know, it was just not something that was even discussed. Like now with Stanford and all these biotech it's the hottest thing. So how did you end up in biotech?
Dr Jennifer Woodell:Thank you. I think I agree with you at the time, maybe it wasn't as common as it is now. I think if I focus specifically on my path, I was at Clemson University and our bioengineering department. And that department had a strong history and focus in orthopedics and also in moving people into industry. So I think I was a bit predisposed to it, but specifically for me again, dating myself, I was taking one of the first courses in tissue engineering at the time. So it was really during the transition from metal and plastic to cells and biology. Just really fell in love with that. Those courses and that idea of regenerative medicine. Of course, we called it tissue engineering at the time approach. And I really wanted to be part of translation from benchtop to patient to bedside. I certainly enjoyed standing at a bench with a pipette, but the idea of actually creating a product was just something I really wanted to do. And in a sense, my first role when I joined industry was very much like a postdoc. I joined our corporate research division and my very first job was in a larger corporation to try to do diligence on smaller regenerative medicine companies to see which ones would be potential acquisition targets or partners for regenerative medicine therapy. And that was such an education for me. Because quite often, the science was really good. It was always a really interesting, cool technology, but there were so many barriers to those things becoming products, dealing with regulatory, manufacturing, clinical study design. Reimbursement on how the product would be paid for it. That piece of translation to a product like I said, was pretty much like a postdoc for me to learn what it takes to bring a product to market in this space.
Dr Karmy:When I was going through, there was no pathway. There was pathway into academia, but there was no pathway that the university would facilitate to go into industry. Maybe, again, off topic, but since you brought it up I've been in pain management for over 20 years, and, it always felt like we're almost there, the stem cells are going to be there to grow new hearts and new lungs, and there's this breakthrough and that breakthrough. But I think as far as I'm aware, there's only one at least stem cell based product that's approved on the market in USA and it's skin. There's no hearts, no kidneys. So since you were understanding, the barriers I guess what do you think, aside from the obvious stuff, like the fact that these products were never there, there's no compensation model that's been established in the way that they are for drugs, that's true for anything new, but it seems like there's also a technical challenge here that's incredibly difficult. So what is it about the field that makes it so difficult to go from one lab bench and there were a ton of very exciting projects, even back 20 years ago, an actual product that works?
Dr Jennifer Woodell:Yeah, that's a great question. I think it's obviously multifactorial. One, the regulatory bodies around the world, but particularly the FDA approach new therapies on a risk based approach. So they're going to weigh the risk of a new, fairly unknown technology against the disease it's trying to treat. So if you think about bringing a cell therapy to market and you're treating a cancer versus knee pain, the risk profile is vastly different. And so that's why we see CAR T cells now But there are still no quote unquote stem cell therapies in any really orthopedic space at all. There is, a autologous cell based product that is cultured and it took years and years to finally get that approved through the regulatory agencies. So that's one thing. The second is really the cost of manufacturing and the difficulty of manufacturing. When we're making metal and plastic parts, we're very tight quality control to ensure that every single piece meets all the specifications and is controlled. We need to apply those same regulations to something that's alive. And so to culture cells and to ensure that we haven't had any genetic changes. There's no sterility issues, all the other things to ensure that every single lot is the same, and it will meet the criteria to treat the patient just becomes exponentially more challenging and more expensive. So then when you're bringing this very expensive product to the market. Again you have to look at what are the alternatives that the patients have. For example, if you're talking about a cartilage injury versus an oncology treatment. So I think an oncology treatment can absorb a much higher cost of goods than something where the alternative is a micro fracture. That is significantly less expensive. Unfortunately the finances do play a role as well, but I think it's just technically challenging to ship, to culture, manufacture and ship. Things that are alive and ensure that they will still work when they reach the patient.
Dr Karmy:So I guess that brings me easily into the next topic. The regenerative medicine approaches that on the market other kinds of approaches that don't require cultures.
Dr Jennifer Woodell:Yes.
Dr Karmy:You take something out of the body and put it right back in. So chances for contamination, genetic changes, all these issues go away, which is where nSTRIDE comes in. nSTRIDE, of course, is one of the newest regenerative medicine approaches. It it only came out in Canada in 2020, and I'm not sure that it's hopefully coming out in the U S. soon in select markets . How did the idea come around, or come up?
Dr Jennifer Woodell:Yeah we the company I was with did have autologous therapies, a point of care technologies, but really focused on platelet rich plasma or PRP, which is concentrating platelets, which have growth factors. So to concentrate those and in various ways to deliver back to the patient. And in the mid 2000s, I was working with a surgeon who was asking about a specific cytokine called IL 1RA, Interleukin 1 receptor antagonist, and asked, Hey, how much of that is in your PRP? And we did a analysis to look for it and there wasn't much. And so I was like, okay, that's interesting. So we started a path to try to find it within the blood, and then how could we concentrate it to make something that was more an anti inflammatory cytokine as opposed to a growth factor, which is soup, which is what a PRP is. And in doing research, we discovered that the major anti inflammatory cytokines in our body are actually produced by white blood cells and not platelets. For that particular cytokine, it's made in monocytes and neutrophils. So we started with the start product of PRP and then ask the question, can we really increase the anti inflammatory cytokines? So we created a second device that contains polypropylene beads. We put the PRP in with the beads, did a second centrifugation cycle, and that output actually had very high concentrations of IL 1RA, which is one of the major anti inflammatory proteins, as well as STNF R1 and R2. And what's particularly interesting about that grouping of anti inflammatory cytokines are those are the exact ones you need to counteract the inflammatory signals in osteoarthritis, which drive the progression of OA. So that began us on a path to use nSTRIDE in mechanism of action studies to see if we can intervene in the progression of osteoarthritis.
Dr Karmy:So the idea came from orthopedic surgeon.
Dr Jennifer Woodell:Yes.
Dr Karmy:So I guess having the ability to access clinicians at the end, combine them with scientists.
Dr Jennifer Woodell:Yes.
Dr Karmy:Where ideas can go back and forth is what I guess tends to work in this particular situation. There's another product on the market called Pro-Stride. Okay. And that's designed for veterinary medicine. Now, it's actually surprisingly common for products that are used in humans to also be used in veterinary medicine. Sometimes some of my patients will mention what they give to their dog or cat, and I recognize it because I give it to humans. Do you know much about veterinary product? Is it related to nSTRIDE?
Dr Jennifer Woodell:Yes, it's actually the exact same product. The company, when we developed it for human use for our first in human trial, we performed animal studies in order to show safety and efficacy prior to our first human experiments. And both were clinical studies in dogs and horses, which means we didn't create osteoarthritis. We actually enrolled patients that had naturally occurring osteoarthritis. And this was important because when you create osteoarthritis in an animal, you end up in end stage disease. And this therapy wasn't for end stage disease. It was for the mid to moderate OA. And that's very challenging to artificially create. So we enrolled real patients. And these animals went back to their owners and both studies were so successful that we contemplated we should sell this in a vet business as well. However, as a human orthopedic company we just weren't really set up for that. So there was a startup company that attained all the rights to our entire autologous therapy line in the vet space. They purchased all the same equipment. So it's all the same human products from the same vendors made under the same quality system. And that company was called Owl Manor Veterinary and recently Owl Manor, maybe in the last couple of years was acquired by Zoetis. So now Zoetis holds the whole product line for in the vet space for global use.
Dr Karmy:So I don't know if you have any access to some of the data in animal studies, and I don't know if they continue to do any research in animal studies. Do you have any sense if animal studies show anything different than human ones?
Dr Jennifer Woodell:So in our animal studies, the efficacy was fairly similar to what we saw in humans with one caveat. In the horse studies. Horses can't go non weight bearing on one limb. So if they have a sore limb, they still have to walk on it. Unlike dogs can be on three limbs with no problem. So we actually saw a better effect in horses than we did dogs, just because they're able to move fine on three limbs. But. Other than that, the cytokine profiles were very similar. And the results were very similar. There have continued to be publications coming out of the vet world and again, very similar results.
Dr Karmy:I guess I think often we don't have great animal models for human diseases. So we end up creating a model for Alzheimer's, because mice don't get Alzheimer's, or, and then we try treating that model, and often works great in mice, but then doesn't really translate to humans. I think in some ways, osteoarthritis is perhaps similar. We don't get osteoarthritis because somebody injects a noxious chemical into our joints, right? Time frame, I think, matters. It is a very gradual disorder. Probably the chemical soup that lives in the joint when you inject the chemical, and it's different than chemical soup from, human osteoarthritis. So You know I guess I always look at veterinary studies where animals developed osteoarthritis as a result of wear and tear the same way that humans do is a little bit more credible than a mice with a chemical injury to the joint.
Dr Jennifer Woodell:Yeah, I absolutely agree that. That's certainly the approach we took. If you, most commonly in dogs, they transect the ACL. In horses, they'll chip out a piece of the cartilage. You end up in a very unstable joint that rapidly becomes end stage disease for osteoarthritis and no injection is going to be able to intervene in that severe case of osteoarthritis. So absolutely, we felt that the naturally occurring. OA examination was best for us, but we lost by doing that. However, these were client owned animals that went back home. So , we don't get histology. And so that's what we lose by doing that approach. So we have in fact done the rat studies where you inject the chemical to create a way and transect the meniscus. And so we can get some decent histology pictures. But again, I think in terms of efficacy I agree with you, that's not very realistic, we really needed the natural OA.
Dr Karmy:And I guess that brings a broader question, is that at least historically in terms of drug pipelines, not talking regenerative medicine here like in terms of DNA, mice and people are very close, I forgot, over 90 percent similarity in terms of genetics if I'm not mistaken. If you go to higher animals like monkeys, it gets even closer, maybe 95 percent or whatever. Yet if I remember correctly, it's very small percentage of drugs that work well in animals that actually work well in humans? Can you speculate?
Dr Jennifer Woodell:Yeah, that's a great question. I probably don't have a good answer for that. Even though I will say specifically for us, we had an added complication in that we wanted to test our product in the animals and our product is not scalable to very small volumes of blood. So we wanted to test our human device in animals. So for dogs and for horses, we were able to draw enough blood and show that the concentrations were similar. Now, that's not the case for every species. For example, we've tried both goat and sheep and by variations in their red cell densities and sizes, we weren't able to get the right concentrations in the output. But when we went to those rat studies, we were not going to be able to get enough blood. So we actually used athymic rats and human blood. So we were really testing the human product in athymic rats, but there's only so much. So like I said we were able to see mechanistically some nice histology, but that's about all we could draw conclusion wise from those studies. In terms of other pharmacokinetics beyond just in general in drug development. I know that you're correct, but I don't know if I have a good reason why.
Dr Karmy:Okay, thank you. The other question that comes out of this is I guess more mechanism related and that is we started out focusing on the growth factors in regenerative medicine. Now, it looks like there's a move towards looking at anti inflammatory factors that reduce inflammation. And the reason I'm bringing this up I was listening to a podcast called All In Summit, and they brought out this guy who was a CEO of salesforce.com. I'm horrible with names, so I don't remember the name, and he's a little bit of a clown, let's just say. And so he was being interviewed, of course it was a business based podcast. I think they were trying to get at what are the plans related to AI in salesforce.com which, makes lots of sense. Everybody's crazy about AI right now. Anyway, of course, they wanted to talk about business, and he started to talk about anti aging and regenerative medicine. And before you know it, he started to talk about how he had his Achilles tendon injected with PRP, which, is fine. It's his shtick. He can do what he wants. He's the CEO of salesforce.com. But then he went on to talk about parabiosis, where you attach two animals together, a young animal and an old animal. And I guess the idea is blood flowing from the young animal will rejuvenate the old animal. And then he started talking about this particular chemical called PF4. Which I guess was isolated from the young animals, and they think that is the factor that rejuvenates the brains, of the older animals. And it was a bit of a disorganized mishmash, but he made it sound like PRP contains PF4. So off I go Googling and I came across this interesting article, now again, articles in regenerative medicine are often interesting enough to ask a question but never big enough to answer one. So this was a really cool article where they were comparing platelet rich plasma injections in athletes against platelet rich plasma injections in regular people. I think they were professional soccer players or something like that. And what I guess the authors have noticed was that athletes seem to respond better to platelet rich plasma than regular people in general, just as a clinical experience. Okay. Let's measure growth factors in athletes PRP and compare it to growth factors in regular people's PRP, right? But in addition to that they threw in a couple of other chemicals to measure. One of them, of course, was PF4, which is how the study popped up in my Google search, and another one was polyp, which is this chemical, I could be wrong, I might have to go back to my article, but it had perhaps something to do with metabolism, nobody is quite sure what it does. So anyway compare the PRP and the weird thing was that growth factors in non-athletes were actually higher, the levels were higher than growth factors in athletes, but what was different via in the other direction? In other words, which things were high in athletes and lower in regular people, was two other things. PF4, which is an anti aging factor, and polyp which is a metabolism agent of some description. So I guess what I'm really asking is, we got the growth factors we're measuring them. We got the anti inflammatory things. We're measuring them. Are there any other chemicals on the horizon that might be worth paying attention to?
Dr Jennifer Woodell:That's very interesting. I only know on the periphery this anti aging. I've probably seen the same type of things that you have. And to be honest I didn't put much stock in it at the time.
Dr Karmy:It does a small step.
Dr Jennifer Woodell:Yeah. I think just in our own experience, when we've been looking at concentrations of factors in a PRP. And the consequential growth factors that come from that PRP we've actually seen similar results that the donors who run marathons and are much more active usually had lower amounts than the rest of us. So that was an an interesting finding. So I think that might, could potentially be a real result. In terms of other factors, I'm sure that is true. However, something that I think for all autologous therapies is a place for improved development is every condition has to be different. It can't be that every single place a PRP is used the same factors need to be concentrated to the same level that just biologically can't be the case. I think, just in developing these products have just tried to, let's get the most that we can at the point of care from the patient and give it back. But I think probably the future would be a little more discerning an Achilles versus an O. A. Injection versus a wound or something like that.
Dr Karmy:Which brings me to my next question. There's a lot of different regenerative medicine approaches, bone marrow concentrates, lipoaspirates, expanded mesenchymal stem cells outside of North America, nSTRIDE, PRP and they all coexist together. Logically, you think if there's one that's superior to all others, then the one that works best would be the one that stays and everybody else would disappear. Why do they coexist? What do you think is the role for each?
Dr Jennifer Woodell:Yeah, that's a really good question and I do think they actually have different advantages to support each. I'll say with the caveat that the regulatory approval and label for all of those devices vary per country and are vastly different around the world. I'm going to give an answer based on the content of what's in the product and the output but not the regulatory label and how it can be used in Canada or the US or in Europe or something like that. In general, I've classified them out into three categories. The growth factors that are in play PRPs are when you have a natural wound that forms. The first thing that happens are that platelets come to the wound site they activate, they degradulate, they release their growth factors, they stimulate the cleanup, and then remodeling, which is collagen remodeling. I think about a PRP in a place where wound healing has stagnated or needs a boost. A chronic tendinopathy is actually where there's a lot of data that supports PRP, but that's a place where collagen remodeling needs to occur and has just not. The wound healing process needs to be restarted in that area. So that's why I think of when I think of PRP. Bone marrow concentrate, quite interestingly, When you take bone marrow and you concentrate it and you put it in agar, just a gel with low oxygen with no other signal, they form tubes. Their signal is to form blood vessels. So when bone marrow concentrate goes into an area with low oxygen, that's a signal to make for angiogenesis. So I think bone marrow concentrate is going to be most useful where you need new angiogenesis. Particularly chronic injuries a vascular necrosis, things like that, where you need new blood vessels. nSTRIDE is the only in that category specific for concentrating high concentrations of those anti inflammatories. So that's why it is primed for osteoarthritis injections. I will say that we have shown that patients who have rheumatoid arthritis, their starting blood is not a good starting material for nSTRIDE because their white blood cells are in fact inflammatory and so the output from nSTRIDE is not appropriate for someone who has a systemic inflammatory disease. So it's specific just for osteoarthritis.
Dr Karmy:What about fat? Fat has contained a lot of stem cells.
Dr Jennifer Woodell:Yeah the other stem cell products adipose amnio cultured MSCs. I have less experience with cultured MSCs, but for the others. Completely my opinion, and I so I'll caveat with that I feel are, in fact, more predominantly producers of anti inflammatories than they are truly regenerative. I don't know if I've seen data where I believe a quote unquote stem cell has regrown cartilage in a joint. But I do know that there are patients who have less pain. And when I. look at the anti inflammatories from bone marrow, they're fairly high. They're higher than what you would find in whole blood. My personal opinion is that these products are varying levels of anti inflammatory products more than they're truly regenerative regrowing products.
Dr Karmy:I guess the other sideline to this is, unlike drugs where you manufacture it in a facility, here your starting material is not identical. Whether you take blood, whether you take fat, whether you take bone marrow, it will be different from person to person. So yes, you concentrate it the same way, but the end result could be very different. So you already highlighted one group that doesn't respond to nSTRIDE because your starting material is too pro inflammatory. Any other groups where starting material matters either in a positive way or in a negative way?
Dr Jennifer Woodell:I think we're going to continue to learn this we're doing, you mentioned AI, we're doing quite a bit of machine learning to try to answer exactly that question, specifically for nSTRIDE. If we look at all the clinical data that we have collected through the years, we pull it all together. Can we start to identify who are the actual true responders and non responders? The systemic inflammatory has really stuck out. So we actually have that as our label that it is contraindicated for those patients. There are other clinical studies and other fields. I know, for example, the patients with for example, critical limb ischemia with that are diabetic, the being diabetic actually influenced the outcome of clinical studies in that space. So I think per indication, we'll see responders and non responders and come out, but at this time, it's still, that's very early For PRP to date, we actually still don't know who are the right responders and who are the right candidates for that therapy.
Dr Karmy:One thing I guess I should comment on, at least my own clinical experience, is people assume that the severity of arthritis and age are determinants. They are, but not to the extent that a lot of people assume. Generally speaking, we're talking averages here, looking at any one individual patient, they could have very severe arthritis, they could be older, and they could have a fantastic response to any of these regenerative approaches. But that's a sideline. But since you mentioned AI, since I have you here. I just not necessarily specifically what you guys do yourselves what do you think AI is going to give the biotech field?
Dr Jennifer Woodell:Oh, it's massive. In the regenerative medicine space, I think The question we've already asked, who are the right responders? Who is the right patient to get the right product at the right time? That takes processing large amounts of data. And I think that's a tool that we will use hopefully to be able to answer that question to get the right therapy to the patient when they need it. And it just expands from there. Across all fields certainly all the companies are looking at varying ways to implement this type of technology.
Dr Karmy:Yeah, I guess I've seen a lot of it in drug development, in data mining as you're doing, but more to find for new uses of old drugs. And sometimes it gives you some really unexpected and fascinating outcomes. So I guess the logical question is, do you guys have a registry? Because clearly, your studies are not going to be tens of thousands or hundreds of thousands of people. AI, is a very powerful tool that often will benefit from lots and lots of data. Do you guys have registries?
Dr Jennifer Woodell:We did have a post market registry study that we ran in the United Kingdom. That study is actually closed and we're trying to get that one published now. So that was a great way of collecting some of this data. The ICRS society has a registry that is free to use and nSTRIDE is in their registry and that's globally available. So surgeons can register on their site and input their data on really any type of injection that they want to use to treat osteoarthritis or cartilage. So that one is available for everyone.
Dr Karmy:So that's just for osteoarthritis?
Dr Jennifer Woodell:It's for cartilage treatments as well.
Dr Karmy:But not to say headache or back pain?
Dr Jennifer Woodell:Correct.
Dr Karmy:And I guess as my final question this is where we are now. I think a lot of people are hoping for 3D printed cartilage stem cells that are going to be glued onto the joint. At this point, you inject them and they float away, unfortunately. There's also, I think, potential for taking, say, ILR2 and just creating a drug. That's just blocking interleukin, right? So where do you think, other than maybe application specific PRP, one for 10, then one, which you already alluded to, where do you think the field are going in the next five to 10 years?
Dr Jennifer Woodell:Yeah, there are a host of companies. in phase two and phase three clinical trials. And I that are really trying to get at not just treating the pain but trying to intervene in the course of the disease. I think if we look at the pathway set by disease, modifying rheumatoid arthritis drugs those have been very successful and they have changed the treatment for patients with RA. And I think that will be the next area that one of these regenerative medicine products, if not more than one, will finally cross into disease modifying osteoarthritis drug. So like I said, it doesn't only just treat pain, but could potentially slow the progression of the disease. I think that's where the this field is going. And I know we're regenerative medicine companies are looking at it and so are big pharma companies to look at small molecules or drugs that could do the same.
Dr Karmy:Thank you for taking the time to speak to me. It was very educational. And looking forward to more new regenerative medicine products. Thank you, Dr. Woodell.
Dr Jennifer Woodell:Thank you so much.
