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 the latest medical innovations, 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 20: Zymedyne and the Search for New Medications for Pain
What is it like trying to discover new medication for chronic pain?
Join Dr. Karmy for an interview with Dr. Chris Bladen, CEO of Zymedyne, a Calgary biotech start-up, to learn what it takes to bring a new medication for chronic pain to patients.
Learn more about Zymedyne Theapeutics here: https://zymedyne.ca/
If you have any questions for Dr. Karmy, feel free to email us at karmychronicpain@gmail.com
Follow our social media:
Instagram
https://www.instagram.com/karmychronicpain?igsh=cHZycXdzeGhqN2Zn
Facebook
https://www.facebook.com/profile.php?id=61550237320641&mibextid=dGKdO6
Send us a text with your thoughts on this episode!
Learn more about pain management treatments offered at our clinic: https://karmyclinic.com/
The reality of especially the drug development business and in particular the field that we're in, which is pain research the vast majority of the money and funding is in big pharma and a lot of that big pharmas in the US. For ourselves I mentioned, we need financing to get through the IND phase. We also are gonna need financing to get to the phase one clinical trials. We're talking tens of millions of dollars , , and it's that kind of money isn't really available in Canada. us, uh, Dr. Chris Balden from Zymedyne and startup company, which is developing a new medical treatment for chronic pain. Hi, Dr. Balden. Thank you for joining us. I guess you introduced a little bit, how did you end up becoming interested in chronic pain? Or was that even what you were interested in? Yeah. Uh, specifically. Getting into pain research. I first started when I began my PhD in 2010 at the University of Calgary. Previous to that, I'd been working in biotech as an electrophysiology and I most of my work was examining iron channels in various other diseases really, such as diabetes and cardiac diseases. But my focus on pain really started when I made it the subject of my PhD, which was to develop newer therapies for pain treatment. So I dunno how these things work, but when I used to be involved, typically your supervisor has grants for certain things and you don't really get to choose a topic. It's sort of given to you and. Yeah I was in a unique situation in that I was working in Calgary as a, electrophysiology for a startup company with my current co-founder. And they were looking at an epilepsy treatment actually. So that was what I was focused on working with the sort of iron channels and the biophysics of diseases is that it's easily translatable across the spectrum of diseases. And so, my supervisor then had grants for a variety of things, including pain. And when the time came and his company actually got merged and actually went IPO, they actually transferred to Harvard University and I had a choice. I either went with the company to Harvard or stayed behind in Calgary to do my PhD or that was the offer anyway, and, and since I had a wife and young kids, I decided to stick in Calgary. I actually, believe it or not, did start looking at epilepsy in my PhD. But many of the same ION channels that are involved in epilepsy, uh, because of the electrical activity, are also involved in the pain signaling. And I quickly became fascinated with the pain story and it, it seemed like a much more, direct avenue to what I was trying to do, which was to I wanted my PhD to be more practical and sort of research focused. and so I pursued the pain, angle and right away it it, it produced a a bunch of papers, quickly. And when you're doing research and you're a student, that's really important. And so once the first one or two papers came out I really started to get this sort of idea and angle into, to looking into pain research and the role of ion channels. so it sounds like the company was an outgrowth of your PhD thesis. Indirectly. It, it was, although, I worked with several other people in the lab that also worked on pain, and it was actually one of those gentlemen that sort of discovered the idea and I worked a little bit on that project as well. So I wasn't directly involved in anything I did in my PhD per se. I was working on actually developing drugs for direct targeting of the calcium channel 3.2, which is the focus of our research. And it was, uh, a few other people in the lab who had a focus on looking at, uh, indirect sort of regulation of the, the T type calcium channel. And it was this research that I had a pretty minor role in. I did some experiments for them, but minor role that led to the discovery and this was back in 20 10, 20, uh, 20 11, 20 12 when this discovery was found. we felt that it was a big discovery, and so we did ask the university to, for help patenting the, the mechanism. But at that time there was really no push to create the company. From that we just, decided to make sure that we patented it before we went about publishing it. So leave the door open for future to leave the door open in the future. Which turned out to be a very, very smart move. So, which brings me to sort of the next stage I suppose. The majority of PhD students, especially in Canada, don't start their own companies in Stanford. Yes. But then Canada usually I think academicians stay in academia. Very few make the jump to biotech technology company. Now, you did have a little bit of background in biotech before you started your PhD, so what led to you jumping back into biotech? Yeah. It's a funny story now. It's quite serendipitous, really. I gave you the earlier background story on the technology and it really sat there patented in no man's land for quite a few years. And indeed as I finished my PhD I was working in industry. I was working with a scientific company after my PhD, but, I also was applying for academic positions and in 2017 I got a tremendous offer from Australia, from Sydney at Macquarie University to join them as a research fellow. And so that's I felt that was what I was gonna do. That would be my academic pursuit. I was gonna be an academic and everything was going quite well with that. Still researching pain. That became my focus in, in Macquarie. But as everyone probably remembers, 2020 something came along called Covid and because I was not an Australian citizen and australia was very strict about its quarantine rules. I came home for a two week visit to my family in March of 2020 and at that point the Australian government closed the door and I couldn't get back. Yeah, so I really felt as many did that I would be losing my job position because I was unable to right away anyway, do research. And so I contacted my old , PhD supervisor, and sort of asked him if there was anything happening in Calgary, that I could work on or work with. And he suggested at that time the university had started this startup program and had some money for that. So he suggested I apply for it. And so I did apply for it based on that technology that I talked about earlier. And we got the grant money and the grant money allowed us to form the startup company . Basically from those humble beginnings we've grown . And it turned out that I didn't lose my job in Macquarie. I was still locked out for two and a half years, but I was able to carry on teaching and doing research and at the same time, fostering the company, and developing it and, helping to get more grants to do the research. And, it's really grew from strength to strength. And me and my co-founder just, we're able to get significant funding for from the Alberta government to take the technology forward at a much faster rate than if it had stayed in an academic setting. Okay, so let's maybe go back and the actual idea behind the company. So is it voltage gated, calcium channel Type 3.2 that you are trying to interfere with. Then there's also an enzyme s o you don't seem to interfere with it directly, but rather indirectly through an enzyme USP five. But I could be getting it wrong, so why don't you correct. Yeah. So in the research lab when I was doing my PhD, they discovered that the 3.2 calcium channel is very important mediator of pain signaling. There are many proteins, of course, involved in the pain signaling process. Uh, ion channels play quite a large part in the signaling where the pain signal gets transferred from the sort of site of injury all the way up to the brain. And CaV 3.2, the calcium channel is quite important in mediating that signal. And what's the lab had discovered is that the increased activity of the CaV 3.2, is enhanced in the various pain conditions. And that when you block that channel either directly or indirectly , by inhibiting them, that causes pain relief. And we took that idea and as I mentioned one of the people who's actually now working part-time for the company as well discovered USP five is also the upregulation or the increasing in 3.2 channels in chronic pain is due to the overexpression of the enzyme USP five. And that this is because the USP five enzyme associates with the 3.2 channel to increase its stability, so it prevents the normal breakdown and recycling in normal physiological conditions. Ion channels go to the membrane and they eventually break down and recycle, and then the normal conditions, there's a certain amount of channels. In the pain condition what happens is that the channels increase and transfer to the membrane so that there's more channels in the cell membrane. And the more channels that accumulate, then the more electrical activity and the more pain signal happens. And so this is caused by ubiquitination being halted. So ubiquitination is this sort of normal, recycling of proteins and what the D U B ubiquitin , enzyme called USP five does is prevent that recycling so the channels keep accumulating and, and so that there's more and more, and this creates the chronic pain signal state. And so what we wanted to do, or what we realized is that if we could prevent the D U B ubiquitin , enzyme from interacting with the channel, it would allow that normal recycling process to occur so that the channel will come back down to its normal levels of physiological function . So that's the beauty of our technology, is that we're not actually directly inhibiting either of the proteins. We are just inhibiting their interactions so that those two proteins continue to do what they normally do. They just don't accumulate like they do under a chronic pain sick. These calcium of course, is very important in many different cell functions from release of neurotransmitters to muscle cell contractions to this particular calcium channel. I'm assuming it's in nerve cells, it's not in any of the supporting cells. What is it? Again, you can correct me. What is its role? C3 0.2 is actually found, throughout the body. It's in, in neuronal cells as well as in the peripheral nervous system as well as central nervous system. Its primary role in the human body. Is it? It's the sort of trigger mechanism for electrical signal. And, especially in the heart and the brain, it controls the rhythmicity. So you know, you have a regular heartbeat or you have original brain signaling. C3 0.2 Channel is thought to be the sort of mechanism that's regulates the sort of continuous, electrical pulsing of both the heart and the brain, . So when it's dysregulated, 3.2 can actually cause arrhythmia and it can also cause diseases of the brain where you get asynchronous activity, for example, epilepsy is the one that I mentioned earlier. C3 0.2 is being implicated in epilepsy, is also being implicated in arrhythmia. Mutations of the channel can cause disease states. So it's very important that's its role in pain has a different role. It's found throughout the pain signal and process from the cells that detect in the nerve endings the site of injury, although right the way up through the, what we call the dorsal root ganglia to the spinal cord and up through the spinal cord to the signaling processing part of the brain. Finding something that can inhibit only in a chronic pain state is, is ideal rather than what a lot of drugs do, which is directly inhibit ion channels and directly inhibit the channel because that could cause other effects on channels that are not involved in the pain processing. First of all it sounds like under least, that the calcium channel almost acts like a pacemaker, and it creates different waves that you see on EEG. There is increase in these calcium I'm assuming, based on animal studies. And the increase isn't just in the brain and isn't just in the spinal cord, or isn't just in the nerves and also ganglia that go to the tissues of the body. They increases actually at all the levels. Yeah we've done most of our studies and show the accumulation in the peripheral nervous system in, in sort of DRG in the spinal cord to show an increase. And again, this is where we feel , the USP five is interacting . We see elevated levels of USP five in chronic pain. We believe that this elevated levels of USP five as a biomarker for chronic pain. As pain is a very subjective feeling and so it's very hard to measure it quantitatively . And so we feel this might be a way that we can at least measure in some way a person's level of USP five correspond to their level of chronic pain and therefore create a more targeted approach for chronic pain patients. But , That's part of the area of our research that's a lot more preliminary. we focus mostly on developing drugs that sort of inhibit the interaction so that we reduce the levels C3 0.2 in, chronic pain. So it sounds like you have, your primary angle and that is to develop a treatment for chronic pain, but also you have a secondary almost stand point where you could potentially develop a diagnostic tool. That could be used in chronic pain management. But one advantage of this approach is that in chronic pain conditions these calcium channels, 3.2 type calcium channels they accumulate, there's more of them than is found under normal circumstances. And the reason for that accumulation is not that cells which transmit pain signals make more of them. The reason for this accumulation is that they're not broken down normally. And your approach is to basically, make it so that they're broken down normally again. Mm-hmm. So it will only affect those cells that have excess number of these calcium channels, but we, this approach will not affect cells that have normal number of calcium channels. Is that right? No, that's exactly right. And that is what we think is the sort of primary differentiator or advantage of our technology is that this mechanism only occurs in chronic pain states. So that it allows us to target in a chronic pain patient. That's what we think is a distinct advantage to our technology, will also decrease the likelihood of of side effects, which a lot of drugs have by directly blocking their protein target. Our mechanism is only found in a chronic pain state . So it will be able to far more discreetly target chronic pain and also not affect those proteins normal physiological functions there's multiple sub categories of chronic pain. As there's neuropathic chronic pain, there's mechanical chronic pain, there's even chronic pain originating from internal organs. What type of chronic pain is this approach targeting? It's a good question and, our research data shows that, that our drugs work on a wide variety of of chronic pain models that we have in our lab from diabetic neuropathy induced pain to chemotherapy induced pain as well as inflammation. Is an, is another one that we are able to have very good animal models of course. We are still in the preclinical stage. We obviously can't test on humans yet and see which specific chronic pain diseases that they'll be most effective of in humans . That's obviously where we're aiming for and trying to get to, but, it seems to work on a variety of different chronic pains is not just the one. I'm not sure how far you've gone with this research, but is it a small molecule that you can swallow? Is it more like a protein or an antibody that has to be injected? It's a small, organic molecule, which we have tested in various animal models. And we've administered it in a variety of different ways but also oral dosing of the animal. We're just in the beginning stages now of testing PK pharmacokinetic profiles of the drugs as to how stable they are and how easily the bioavailability and distribution of the drug is, in the animals. For that, we're using independent companies to, measure this how the drug is distributed and excreted and how long it stays in the system. And those results, will determine the dosage. Our goal is to try and produce a one a day, orally available pill that'll be effective for, 12 hours or more . And that's the target, but the results will guide how that works. And , we have several lead compounds right now that we're developing and we'll go forward with the best one that most closely hits those different targets. But we are aiming for something that's gonna be orally available. Does the medication need to penetrate blood brain barrier? That's the indication that's happening by oral administration that it works. So I would suggest it does. But that is part of what we're testing right now, or we've sent our compounds to be tested to, uh, A CRO to test exactly those things. How the drug is distributed and how long it stays in the bloodstream and system how quickly it's broken down and excreted and, and so on, so forth. Now I you mentioned animal studies and I guess there's animal studies, there's typically human studies, and then there's another methodology geo that I guess was developed in the last maybe 10, 15 years, and that's organ in a chip or organoids where you can actually take human cells and behaves a little bit more like a human liver or a human heart or human brain. And test medications on that instead of animals with the idea that perhaps a, I suppose it's more efficient, theoretically. And because you don't have to, store animals and cages and all that sort of stuff, and b, presumably the results would be closer to what you'd see in human trials because these are human tissues. I don't know if you have any experience with that. I think it's a it's definitely worthwhile., More results you gather, the better. We have sent our drugs to be independently tested to a company that does safety, cardiac safety profiling for drugs, which is of course a very important first safety step. And what their system is they've developed to, differentiated human cardiomyocytes. And , so those are human cardiomyocytes that they basically grow in a dish and then they basically squid our drugs on to those cardiomyocytes and, and see how they react to the drug, whether it changes the action potential or the sort of rhythmicity and I'm pleased to say that our drugs came through with flying colors , that they did not have any impact on those human cardiomyocytes cells. And that's definitely a good result. But getting the results back from live human cardiomyocytes gives us the confidence that that our drugs are safe from a cardiac point of view. So I think those are very interesting. I'm not an expert on organoid development. It's definitely growing and I believe, we're at the stage now where a lot of this testing that I mentioned, the safety toxicity pharmacokinetics is all done independently now by CROs, and they are the ones who do the testing and whether they use animals or organoids,, the results will tell us what they do and, there are requirements from the FDA as to how our drugs will be , and it has to meet those requirements. So, so I I have no idea if f all of the organoid testing meets those requirements yet. So you want to be as close to human conditions as possible before, of course you administer the drug to human. I guess couple of things I'm picking up from here. One is regulation. This is a very regulated field and a lot of what you do is dictated by what FDA or Health Canada says is required before you can proceed to the next steps. So it's not just about what works best, but also what actually meets the regulation. Because even if something can work better, you're not gonna do it if it doesn't meet the regulation that allows you to move on to the next step. And which brings me to the next, question, and that is, how far away are you guys from studies in humans? That's, it's a good question because it depends a little bit on, on how quickly we can get the financing done to sort of complete all this safety testing, the regulatory safety so that we can meet the investigational new drug designation from the FDA. So we are in what they call the IND enabling phase, the investigational new drug enabling phase where we have to do all the safety and toxicology and pharmacokinetic testings. So that requires a lot of money to get there because all these tests have to be independently done by CROs. If we get the money we believe that we can get these results and apply for IND designation within probably the next, 18 months and once we get the designation and, part of that designation is to come up with a plan for phase one human clinical trials, but you can't go into phase one until you have all of the other safety tests done and get your IND designation so that you can begin to do that. And then of course it takes quite a lot of money to, to perform a human trial as well. In a perfect scenario if we can get IND designation we could potentially be doing human trials in the next, two to three years. But it, it all depends on the financing. Hopefully we don't hit any roadblocks. Yeah, startups, of course. How very much affected or limited by the funding. Yes. And developments inside the big pharmaceutical company startups are much more sensitive to funding. So I guess assuming everything goes well and you end up having a human trial and the human trial is successful. I, I don't know that I'm aware of any Canadian based pharmaceutical company that, I guess stayed in Canada headquartered in Canada, and is you know, successful. Mm-hmm. I've seen some companies that get bought out by US or European pharmaceutical companies once they reach a certain stage. But I've never really seen one that's actually stayed independent and ended up headquartered in Canada. Any thoughts? I have lots of thoughts on that. The reality of especially the drug development business and in particular the field that we're in, which is pain research the vast majority of the money and funding is in big pharma and a lot of that big pharmas in the US. For ourselves I mentioned, we need financing to get through the IND phase. We also are gonna need financing to get to the phase one clinical trials. We're talking tens of millions of dollars , , and it's that kind of money isn't really available in Canada. It's very hard. And so we realistically, if we wanna see our technology to progress, we are gonna have to at some point, either license or partner with a big pharma in the US or somewhere else. US obviously would be the most obvious choice 'cause it's close. If, if the end goal is to develop a drug that's actually gonna be effective and make it to market and it's gonna help millions of people with chronic pain, it takes hundreds of millions of, of dollars and for a startup that's not really realistic. Even if you are able to stay independent from a big pharma the money that would be needed to raise to do that is more likely gonna come from the US as well. I think we are realistic enough to know that with the amount of money involved and the logistics involved as well, have taken a drug all the way to market. It takes a company with deep resources to do that. and for startups it's not practical or realistic. in our field we struggle to find the money . They call it the valley of Death, what we're going through because it's so difficult to find financing for the preclinical stage. Once you get into human trials, then more people are interested in funding it, but then, your technology is much more mature then, so the risk is less. We do get certain amount of backing from governments , and we get certain amount of funding and backing from the University of Calgary too, but. The kind of money that we need In order to succeed far exceeds what they can offer us. So we'll end here. I thank you, Dr. Balden, from taking the time to speak to me and best wishes for your startup. Certainly we need more pain medications. We have very limited number and most of them have been around for about 20 years, it's, I just think it's wonderful that more people are trying to develop new treatment options for chronic pain. Thank you. Yes, thank you. And thanks for having us. So what are my final thoughts about Zymedyne? Obviously. The market for a new chronic pain medication is huge as 20% of population have chronic pain, and the medicine has a potential to be a breakthrough in the field. It doesn't just act on the spinal cord, but potentially can act at other parts of the nervous system involved in processing pain signals. So far, it appears to be safe, however, the question is will this company succeed? And if it does, will it stay in Canada or move to the US. Historically a lot of great medical discoveries have been made in Canada. That includes discovery of stem cells, discovery of insulin, even discovery of the chemical pathways that led to development of ozempic. However, commercialization of these discoveries. Happened in other countries and the windfall that accompanied these discoveries again, stayed with countries who are good at commercialization, not necessarily countries who just discover new medical facts. So Canada is very good at funding basic research and nurturing, , scientists and allowing them to pursue, sometimes topics that are not popular., It is also arguably pretty good at funding startups at the point when they're created. What it fails at, however, is growth of these startups. Typically, , companies in Canada can get access to money in tens of thousands or even hundreds of thousands range. But as you heard during the interview for a company to produce a new drug, it'll likely take $150 million just to get to that point that it becomes sufficiently far along that other outside sources will invest significant sums of money. There is a statistic that it takes about a billion dollars to bring a drug to the market. So in my mind, the question is how can we make it so that Canadian discoveries become commercialized in Canada and we create companies that stay in Canada. Well, unfortunately I don't have a simple answer for that. However, I have some possible thoughts of a solution, uh, perhaps instead of providing small , grants to multiple startups we should develop an area of expertise, so that we can provide much bigger grants, but to fewer startups. As you heard during the interview, smaller countries have less money than big, wealthy countries like US or China, and they cannot compete financially with those countries and everything. However, if they focus on a specific angle or specific part of, uh, the medical field, perhaps they can outcompete bigger countries in that small field. Another possible solution to compliment my first idea is to create an environment where we can attract major American and possibly Chinese VCs. Governments are pretty good at funding basic research and at providing money to very early startups, but they are notoriously bad when it comes to growing a company. And I think part of the problem is that, uh, government administrators are not sufficiently incentivized to make sure that the companies their funding succeed. In partners in VC firms the VC stands for venture capital I. On the other hand, live and die on the basis of success of companies they invest in. If every single company they invest in goes bust, the VC firm will be out of business. So they incredibly incentivized to, uh, not just invest money in companies, but also to make sure these companies succeed. A lot but not all VC firms, in addition to providing money, will have a seat on the board where they will often mentor first time founders of startups as well as open the doors for them. As well as helping with recruitment of qualified employees. So VCs don't just bring money and appetite for high risk, high return outcomes. They bring smart money, which actually increases the chances for the company succeeding. Finally, the government would have to create some kind of a keat and stick tax environment, which would encourage VCs not to move the company to the US once it reaches a certain size, but rather leave it in Canada. For too long, we have been too dependent on the US. For too long we have also been very dependent on our natural resources. And while US economy is primarily driven by tech, our economy is still driven by the same industries that drove it in 1950s, I think at this time for a change. Thank you. Disclaimer when it comes to your health, always consult with your own physician or healthcare provider for personalized advice and guidance. The information provided in this podcast is for educational and informational purposes only, and should not be considered medical advice or a substitute for professional medical care. Be sure to follow our Instagram at @karmychronicpain for updates on new episodes and more educational content today.
