Latest / BioSpace / Rewriting the rules of CMV prevention
Transcript
- speaker-0: My name is Jennifer Smith Parker, Director of Insights at Biospace, and you're listening to Denatured. In this episode, you'll hear from Ian McGowan, Chief Medical Officer at Sinclino, and James Hunter, Associate Professor of Transplantation, Oxford University. We explore transplantation and antiviral innovation and why CMV remains one of the most persistent and consequential challenges facing transplant patients today. Ian and James, thank you so much for joining this episode of Did Natured. And Ian, if we can go ahead and introduce yourselves and James will follow. speaker-2: Sure. My name is Ian McGowan. I'm the chief medical officer at Sinclino, which is a Danish biotechnology company, where we're really focused on developing an innovative strategy to really try and prevent ⁓ cytomegalovirus infection or CMV infection occurring in patients after they receive their new kidney transplant. So looking forward to chatting to you a little bit today about this problem. speaker-1: Yes, thanks very much Jennifer. I'm James Hunter. I'm an academic transplant surgeon. have an interest in organ perfusion and organ preservation. So we have a research program where we pump organs ⁓ in an ex situ setting outside the body with warmed oxygenated solution so that they reanimate. And it's a technology that enables us to test the organs and provide therapy skin interventions. Also I'm the National Clinical Lead for the Kidney Assessment and Recovery Pilot, which is and innovation through NHS blood and transplant where we're aiming to try and increase utilisation or utilisation of organs through using this technology that I've just described. And I'm very interested and looking forward very much to the discussions today about how we can potentially use that in CMV disease to help minimise it. speaker-0: Perfect. Well, thank you so much again, both of you. So let's start off to define CMV for our audience and why it remains a persistent issue in transplant patients. speaker-2: So maybe I can I can just start off and James, please chime in. CMV or cytomegalovirus, it's really a common virus. If you look at different populations and different ages, between forty and ninety percent of people have CMV. And it's one of those childhood viral infections you acquire and it remains latent, quiet, doesn't cause any problems usually, unless you become immunosuppressed. That can either be due to disease. And you may remember the sad days of HIV AIDS when patients would develop CMV retinitis or CMV colitis. Or it can be what we call atrogenic due to the therapy a patient's receiving. And that's the classical situation in transplantation, where we immunosuppress a patient to prevent rejection, but that then under certain circumstances can allow viruses such as CMV to reactivate and cause problems. speaker-1: Yeah, absolutely. mean, and this is an issue that is, it's relatively common and it's not always straightforward to treat. The treatment that we give has significant implications. It can cause things like bone marrow suppression and result in patients having unnecessary infections. And also the treatments are not that well tolerated by patients who are already taking a big cocktail of drugs after transplantation. This is another one to add to it. So concordance or compliance of medications also becomes a potential problem. So there's this balance that is very challenging and it's interesting because transplantation, know, the transmission of disease is something that is sort of accepted as part of the process because it can't ever be risk free. And CMV is just one example of a virus that's problematic, but there are a number of others as well. speaker-0: Where do current antivirals fall short, therefore, particularly in preventing reactivation? speaker-2: Well, I think James has touched on some of the problems, but maybe to give some context. Generally speaking, you can have an organ which can be CMV positive or negative, and you can have a patient who can be CMV positive or negative prior to transplantation. And when we have a scenario where a patient who doesn't have CMV receives a kidney which is CMV positive, they have to, generally speaking, will go on something called universal prophylaxis, which we means shortly after the transplantation. They start taking the drugs ⁓ James is alluding to. One example, the most commonly prescribed drug is polyvalgancyclovia. And in that setting of donor positive, recipient negative, in theory, they should receive that drug for up to ⁓ six months following transplantation. Wow. And the problem is that represents a significant adherence burden for the patient. It's also a drug which is known to be associated with a fall in white blood cell count or leukopenia. And that can happen in up to 40% of patients. Comes a very significant clinical management problem. Do you cut back on the immunosuppressives? Do you give some colony stimulation? Do you what what do you do? So that's a real problem. And then finally, even in the most recent studies of the most recent CMV drugs, about 30% of patients, despite taking the drugs, will reactivate ⁓ their latent reservoir and have activiral replication. And overall, about 10% may run into problems. real CMV disease, which in and of itself can be a challenge, but it can also increase the risk of graft rejection, ⁓ hospitalization rates go up, economic burden, and sadly a small but measurable increase in risk of mortality. So it's n something you really want to prevent, but current strategies are not really doing the job fully. speaker-1: Yeah, I mean, absolutely I fully second that and it's classically a disease that's really quite difficult to diagnose despite the fact that we can measure the levels of the CMV DNA in the bloodstream, which gives us a reasonably accurate measure of how significant it is. People present after transplantation with often very, very non-specific symptoms and they can become quite unwell before it's picked up. So it's a real problem. CMV can cause disease in many many sort of body systems. So, know, Ian alluded to the retinitis. So they have problems with their eyes. You can have problems with the GI tract. you get a colitis which causes, may or may not cause diarrhea. It can affect the liver. So CMV really is a disease is very nasty and has a genuinely quite alarming significant impact. speaker-0: And it tends from what you're talking about here the clinical burden of CMB reactivation. So for transplant patients and care teams, it sounds as if there's a lot of resources that would be coming into that. speaker-1: Yeah, mean, obviously patients are followed up quite closely in the clinic, but the drugs cost money. Every time we do a CMV test, it costs money. Every department will have their own protocol as health and they measure CMV levels in what type of patient. yeah, I mean, from a patient perspective and from an NHS resource and cost perspective, it is something that has implications and potentially delivering these therapies. If it has the possibility of minimizing or even alleviating this problem, that would be a real advantage. speaker-0: Ian, let me ask you with Sinclino, is it is targeting the latent violar reservoir rather than active replication? Can you explain that to the audience a little bit more in layman's terms and why that could be a fundamentally different approach to managing CMV? speaker-2: Absolutely. So as we talked about a little bit, when when individuals first become infected ⁓ with cytomegalovirus, they're viremic, they have an illness, or it may be very, very mild, or it may be as asymptomatic, but then the virus just hides away. And it hides away in a subset of white blood cells at very low incidence. Very few cells are actually infected. But that's the reservoir. Now, current therapies on drugs like Valgancyclovir or Latermavir or Maribavir, these drugs only work when the virus has started replicating, it's going through cycles of replication and the drugs are are used to hit various enzymes associated with viral processing. That's how they work. So they only work once the virus has escaped, if you will, from the reservoir and is replicating. And because of that reason, they're not, as I said, entirely successful in preventing full viral replication or even even disease. So what we're trying to do at Sinclino is a completely different paradigm. What we're saying is, let's go after the latent reservoir. Now, how do you do that? Well, it so happens that when viruses infect cells, they often bring some of their genetic material with them that end up being expressed as cell surface receptors. And in the case of cytomegalovirus, CMV, there is a receptor called US twenty-eight. It's like a badge of honor. Any CMV infected cell will have that receptor on its cell surface. Whereas healthy normal cells without infection won't. So of course that became becomes a target. And what we've done is to design a drug which will actually bind to that receptor. The drug receptor complex will then internalize into the cell. ⁓ it will then undergo cleavage, as it were, and release a payload, a toxin, which will then induce that cell to undergo cell death or apoptosis. Net result. We take out the latent reservoir of cells, which no current therapy can do. So that's kind of a paradigm shift. The second paradigm shift is, as I mentioned, normally in transplant practice medicine, the antiviral treatment drugs used to try and prevent CMV disease are started after transplantation. Our intervention is before transplantation. So when the organ is procured from the donor. The organ is put on a perfusion device, the type of device James will tell you about in a minute. And as the organ is being perfused, we add our drug. And so the drug is circulating around the kidney for up to four hours. And then we wash the whole system, we perfuse the whole system. And based on our preclinical studies, and we hope we'll be able to show this also in our clinical studies, there is no drug left. So when the organ is transplanted into the recipient, We hope that we will have significantly reduced the latent reservoir of CMV and also there is no drug left in the kidney. And that's a very attractive and and innovative proposition really from a drug development perspective. Because of course you don't have to worry about toxicity of the drug if there's no drug when you give it to the patient. So that's why I think ⁓ our approach is so different. And ⁓ we were very excited we were able to publish ⁓ earlier this year quite an important paper with our collaborators in Cambridge. Which showed that when we did this, we perfused CMV positive organs with our drug for four hours. And then we looked at the change in the latent reservoir. We were reducing it by a more than ninety percent, which we think is gonna correlate in the clinic with a significant benefit. So this is why our drug is it's just a very different ⁓ approach, ⁓ and an exciting approach, I would argue. And I should mention briefly we're talking about kidney today, but we already we already have data in lung showing the same benefit preclinically. And in theory it could also be used in liver. So this is quite an opportunity here. speaker-0: When we're talking about this opportunity, I want to go back to two points that you mentioned earlier. First, I would say is the side effect with the current CMV treatments like myelosuppression and tolerability. And I'm wondering in this population, is this particularly crucial to be addressed about the safety and tolerability because they're already fragile? speaker-1: Yeah, absolutely. And as I alluded to earlier, patients are on a large number of medications, particularly in the first six to 12 months after transplantation. And yes, the kidney transplant dramatically improves your quality of life, but medication tolerance and medication adherence is an issue. The more medications people take, the more likely they are to miss some. in particular, there's a number of drugs or medications that people have to take that also can cause bone marrow suppression and reduction in your white blood count. And if you're on a series of these drugs, then it's even more problematic. any way of being able to modify that. And if this therapy that Ian's very eloquently describing can say even move a reasonable portion of patients just to being under surveillance rather than on therapy, that would have a really significant impact, I think, on people. speaker-0: I'm also wondering, James, from a transplant perspective, from a surgeon perspective, how do CMV risk and broader post-transplant complications factor into decisions about organ utilization and patient management? speaker-1: Yeah, well, that's big question. speaker-0: Yeah, it's a big one within this within this one. Big big answer within the one question. speaker-1: It's important organ utilisation, particularly in the UK, Northern Europe ⁓ is challenging because the donor population is aging and people have got more medical conditions such as diabetes, high blood pressure, heart disease, obesity is increasing an issue. So the population of donors we're seeing is more marginal. Selecting a donor from that perspective for an adequate recipient is what transplantation is now about really, because also that the transplant waiting list, the average age increased. It's not people with genetic conditions, young patients with intrinsic kidney conditions. It's older patients with kidney failure secondary to other conditions such as diabetes. That's a shift that's happened over the last 10, 20 years. And the waiting list has gone up. The number of donors has gone down. So we're increasingly trying to make sure that we can find a suitable organ for a suitable recipient. Does the CMV specific issue come into play? And that's where this is interesting because no, it doesn't when you're making a decision about an organ. Other things do, but not CMV in particular. So we've almost taken it as acceptable that we transplant CMV into a recipient because otherwise you would be restricting the number of organs for people and it's not something we can do. So the transmission of disease and the risk never goes away in transplantation. It's just about balancing how you manage that. And you wouldn't want to deny a patient an organ just because they may be a CMV negative patient and this is a CMV positive donor. speaker-0: What you're saying in that is you can go ahead and take away that CMV risk from the very beginning. speaker-2: Ex exactly. So I think what what what what James has ri laid out very clearly is the the crisis, as it were, that we have in transplantation is this gr this growing gap. And so, you know, every transplantation has to be optimized and we have to do everything we can to try and minimize the risk of that transplant failing. So that's the other side of the equation. So as I alluded to, you know, James said, you know, we can't prevent possibility of CMV organs being transplanted into into patients, but we can perhaps do a better job of reducing this particular risk. Of course there are other risks associated with transplantation, but at least this modifiable risk of CMV we can we can explore using this kind of perfusion strategy. And I think another benefit in principle is and James is the expert here, he may touch on this in a minute, you know, the increasing use of perfusion to rehabilitate, regenerate organs is is is also a game changer. And in a way we're piggybacking onto that. So now the two things together are very complementary. So I think there's we're going to be seeing more perfusion, maybe more normothermic perfusion. And we're beginning to see drugs. I think we're probably one of the f one of the first, if not the first, drug that's actually gone into clinical trials. So this is a very new field of science now. speaker-0: I mean, speaking of perfusion, a perfect kind of segue to that too. So with the ARC programs that they aim to expand that bone that donor pool with perfusion technologies. So I'm trying to understand better of how transformative that could be and addressing organ shortages and discard rates. speaker-1: Yeah. And so, well, mean, NHS Blood and Transplant who are driving this initiative with support from the Department of Health financially have predicted that we could be increasing transplant numbers by up to 750, which is sounds like an astonishing number. And that's the aim of the program is it goes through the pilot phase where There's a pilot program in liver, in lung and in kidney. So we've got three different arms of this clinical pilot. And over the next 18 months, the idea is that we have centers in the UK who've got expertise in pumping these organs with a warmed blood-based oxygenated solution so that we can assess their viability during that period of time. And it certainly has the potential to be transformative and it's a really unique opportunity to be involved in this program. There's about 400 kidneys in the UK each year that are retrieved for transplantation, but actually never transplanted. And it's due to a number of factors, but a lot of it is about clinician uncertainty. They're worried that this organ won't work. Even though they've previously decided it looks okay, actually there may be some small other factors that have happened during the retrieval process, which makes people anxious. The idea of the AHRQ program, Assessment and Recovery Center, is that we give people confidence by saying, We've perfused this organ for six hours. The blood flows are good. The organ looks good. It's clearing metabolites such as lactate. We think this organ is going to work. And so if we can just give people a bit of additional confidence, then we can improve organ utilisation. And if you just take this beyond the UK, now in the US. It's somewhere between nine and 10,000 organs that have declined each year that have already been retrieved for transplant. So we're talking big numbers that can have a big impact on the weighting. speaker-0: ⁓ big numbers at nine to ten thousand just in the US. That's speaker-1: It's astonishing numbers and you know, this leads nicely into, know, what can you do to an organ that is being pumped on a device? Well, as Ian correctly says, and as they've tested very elegantly in Cambridge, you can deliver these therapies. And this is just one such example. There's examples of other therapies that can be delivered during perfusion to have an impact on what the organ might do after transplantation. And so if we can give the the anti-CNV drug during perfusion ⁓ and whether that would link with an ARC or whether that would link with local centre practice doesn't matter. It's all for the same objective and I think it's a really exciting time to be involved in this sort of project. speaker-0: Well, in that end, that's a great way to end it about an exciting time that we have for the for a new technology and for this project. So thank you so much, Ian. Thank you so much, James, for joining this podcast. Really interesting to hear about the advancements, but particularly to tackle CMV. And if you'd like to listen to more episodes of Denatured, please turn to biospace.com and feel free to shoot me a pitch idea at jennifer.smith hyphenparker at biospace.com. Thank you very much.