S5, E05: H-Guard®: Improving Physical and Mental Health

Andy Herbert (00:00):
When I got into this whole idea of starting to take my fundamental research to clinic, because I got slightly jaded, saying when I was writing academic grants, saying that, "This can be used for that," and the other, and it'll be amazing and it'll save the world. I decided that I was going to put my money where my mouth was and actually try and do it, and so with that in mind, you look around the space, and although there is an awful lot of innovation in the sort of pharmaceutical and therapeutic world, generally, in the case of patients who've got kidney failure, particularly dialysis, hemodialysis and peritoneal dialysis, the innovation has stalled.

There's been nothing to really differentiate the various different companies on this, so what I would like to say to any patients who are in this situation is that we at least are working as hard as we can to bring new treatments to you that will hopefully improve your quality of life, and it will also extend your life as well. I guess I want to say hope is coming, and I'll certainly work my as hard as I possibly can to make that a reality, with the ultimate goal of helping as many people as possible with as many different disease conditions as we can address.

Gina Mullane (01:41):
Chronic kidney disease affects 10% of the world's population, approximately 850 million people, and is growing by 6% each year. Despite recent improvements in hemodialysis therapy, inflammation, and complement activation remain a common byproduct of treatment. In fact, nearly half of dialysis patients made a tragic end due to cardiovascular complications, but what if there was a way to combat the often deadly side effects of hemodialysis without interfering with its efficacy? I'm Gina Mullane, and in this episode of Vital Science, we sit down with Dr. Andy Herbert, co-founder and CTO of Invizius. We talk through the company's groundbreaking H-Guard technology, their unique development journey, and the inspiration that came from the loss of one very special dialysis patient.

Todd Poley (02:39):
Welcome to Vital Science, Dr. Andy Herbert. We're honored to have you. Would you tell us a little bit about yourself?

Andy Herbert (02:46):
Hi, Todd. Thanks very much. Yeah, so I'm an immunologist and a former academic. What really used to interest me was how microbes in particular invade the immune system. Then, shortly after studying this, it occurred to me that we could use some of the insights that we got from studying how pathogenic microbes abate the immune system and use those to turn into therapeutics or treatments for patients, and so following probably the best part of 20 years in academia, I co-founded Invizius with my colleague, Richard Boyd, and basically my job is to oversee the whole of the science platform here at Invizius, and in particular, to try and use the insights that we've gained from understanding how the immune system is regulated, how things can evade the immune system, and use that as a way of protecting patients, either from treatments or diseases that cause their immune system to be overactive. The one we're going to talk about today is chronic kidney disease and dialysis in particular, which is a major killer worldwide.

Todd Poley (04:07):
So Invizius has a really interesting story around its beginnings. Can you tell our listeners about its origins?

Andy Herbert (04:14):
Sure. So probably 20 years ago was when I started first investigating how the immune system is regulated and how microbes really managed to hijack the body's own defenses to help themselves. With a fairly gifted team, we managed to come up with some understandings of the mechanisms by which this is done. And so, after filing a patent or two, we span the company out of the University of Edinburgh back in, I believe it was 2018. Shortly after we span out, a gentleman called John Prosser got in touch with us through the university's website, and we set up a meeting. He told us about his daughter, Allison, who unfortunately died through some of the complications associated with the dialysis treatment that she was on, and he was very keen to be supportive and to use Allison's legacy and memory to try and help the next generation, if you like.

Todd Poley (05:26):
Yeah, so I've read about Allison's legacy, and what an inspiration it's been for your company. You mentioned helping the next generation avoid these same complications. Can you help us understand H card's mechanism of action and why you refer to it as a second generation therapy?

Andy Herbert (05:44):
Yeah, so what we do at Invizius is we learn how to appropriately control a certain part of the immune system. It's called the complement system. There are drugs and therapies in current use. And these are what we term the first generation. Pretty much, by and large, what they do is they're a bit like a sledgehammer to crack a nut, so they shut down the whole of this part of the immune system and don't allow it to do its other jobs. It has roles in all different types of immune surveillance, so it's there for removing cells that are dying or distressed. It's there for cleaning up all sorts of rubbish and keeping the body really healthy, and these sorts of first generation therapies just kind of shut that off at a particular point in the pathway.

Now, what we've done is we've done two things. The first thing is that our primary technology works by enhancing the body's own complement regulators. Secondly, in addition to this enhancement of a normal effect, we have the ability to move and target the host regulators onto the surface that needs to be protected. In the case of chronic kidney disease, it's the artificial kidney, the dialyzer that causes an immune response, because they're very large, they're foreign bodies, and the body naturally goes and says, I want to attack you because it thinks it's under threat. So what we do is we move the body's natural regulators from where they are normally, which is floating around in the blood, and localize them onto the foreign surface that we're trying to protect. What this means is that we're working with the body rather than against it. Instead of having this big sledgehammer to try and crack the nut, we're just tweaking things, moving things where they need to be, and making them a little bit better than they otherwise would be, but apart from that, we're trying to be working in harmony with the body.

Todd Poley (08:01):
It's really interesting. I've seen, in some of your presentations in the past, that you almost reference it as a invisibility cloak, which I thought was a very interesting way of describing it.

Andy Herbert (08:13):
That was one of the things that we used right at the beginning, was that analogy of the invisibility cloak. Indeed, that's where ultimately the company's name comes from. It's a sort of modification, a [inaudible 00:08:28] version and a Latin derivative of invisibility.

Todd Poley (08:33):
That's a great thread for us to follow. Can you tell us a bit more about this invisibility aspect and how complement therapy works?

Andy Herbert (08:42):
Sure. I guess, as I've already said, what we are all about is trying to make something that's foreign appear invisible to the immune system as a whole. If you imagine a dialyzer, I don't know if you've ever seen one, but they're these really large bundles of fibers that you pump the blood through and all the toxins go on the outside and the blood goes through the middle, but in order to do their job, they have a really, really large surface area. It's about two square meters, which is about the size of a medium-sized dining table. If you compare that to the size of a microbe, which the body can pick up instantly as being foreign, this is really quite a large thing to try and hide. And indeed, naturally the body picks it up, recognizes it as foreign, starts an inflammatory, and an immune response against it.

And so what we've tried to do is, part of the work that I did looking at how pathogenic microbes hide from the immune system, we discovered one of these molecules that, what we call PSPCN, and that has the ability to enhance the body's own natural regulators. It makes them better at their job, but in a way that is actually how the body uses itself to discriminate between itself and something that's invading. So we have this part of the molecule that enhances the body's natural compliment regulators, and then we stuck on an extra bit to it, and that makes it sticky and able to bind to the surface of the dialyzer. And so what basically happens is that we pass the H-Guard solution through all the blood contact surfaces, including the dialyzer before the patient's blood comes into contact with it.

The H-Guard solution, or at least the active molecule in the H-Guard solution, then sticks to the dialyzer, and then immediately upon contact with the patient's blood, it pulls out complement regulators from the patient's blood and coats the whole of the surface in these complement regulators, and that has two effects. One is it makes the surface look less foreign, because it's coated in a normal human protein, in one of its normal confirmations. Secondly, because it's a complement regulator or an immune regulator, any sort of residual immune reaction that they get is then quickly dumped down, so you don't get the sort of amplification and all of the downstream effects. It's just, "Oh, yeah. We see you. It's all right. Nothing to see here. Everything's fine," and that's generally how it works.

Todd Poley (11:41):
It's great to understand the differences between first and second generation therapies. I know H-Guard is focused on combating complications for these patients like cardiovascular disease. I've also read that complications can arise from the mental health perspective. Can you speak to that, the link between dialysis and mental health?

Andy Herbert (12:02):
Yeah. Now, this is something that's absolutely fascinating, and it is well known that patients who are receiving dialysis treatment are generally slightly depressed. And most people pull that down to the fact that the therapy itself is a really fairly hard regime. I mean, you think about it, they by and large go to a hospital or a clinic three times a week. It takes them an hour to get there. They, then, sit on this machine for four hours, and then it takes them an hour to get home. The treatment itself makes them feel a bit unwell. Just before they go on, they feel unwell as well because their kidneys don't work, so they haven't been able to remove all of the toxins that the kidneys otherwise were doing and removing urine, and so everyone has, for a long time, just assumed that the reason for the relatively poor mental health of dialysis patients is all down to the regime they're in, after all, who would want to be in that if they didn't have to and they had no other choice?

But as in so many things, the truth is both more fascinating and also slightly darker. So one of the problems that they have when they're on the dialysis treatment is that they become more inflamed, so the immune system recognizes the dialysis filters as foreign, as I said, and you get all of this excess inflammatory burden on the patient. It turns out that this increases the propensity to feel things like depression. It's quite interesting. I ordinarily thought that most people have a way, that their natural sort of chirpiness, if you like, it's kind of ingrained. We've all seen when something happens, people get miserable and then bounce back, or if they're miserable and something good happens, they're happy for a while, and then they reach their norm. But what it seems in the case of dialysis is that it's the treatment itself and the inflammation that causes, that then leads to negative impacts on the patient's health. So it's almost like the inflammatory system is talking to the brain and making the brain more prone to some mental health issues.

Todd Poley (14:31):
Yeah. It's clear that dialysis can cause quite a strain on the body and the mind. It's also necessary for so many people with chronic kidney disease. So what does access to treatment look like for these patients, both for dialysis and for a therapy like H-Guard?

Andy Herbert (14:47):
So H-Guard comes in a very, very strange niche. So in Europe, we're regulated as a medical device. In the USA, we're regulated as a drug. If you think about it, we're kind of both, so we have an effect on the patient's immune system. So that clearly makes us a drug, but we're not treating the patient, we're treating the machine, and that sounds like we're a device. It puts us in this very strange regulatory position. I mean, from H-Guard's point of view, it doesn't really matter to us per se which we eventually come down to.

The only thing that really matters that to me is that patients who need the treatment can get hold of it. In the originations of the world, that is at least possible. In the poor nations of the world, the cost of dialysis itself is already such a burden on the healthcare systems, that people are apparently unwilling to want to spend any more than that. It's always been a race to the lowest price, shall we say. So instead of having innovation and improving the treatment for the patients, it's very much been all of the innovation has been focused around reducing the cost, and I think that's slightly unfortunate for the patients.

Gina Mullane (16:23):
The medicines and healthcare products regulatory agency or MHRA has given Invizius the green light for their first inhuman trial, marking a major milestone in the journey from concept to clinic. This trial will take place in Manchester, with up to 10 patients receiving a single exposure to H-Guard to ensure safety and also to assess potential positive effects. Invizius has a unique focus on identifying patients with angry blood, those who struggle with dialysis due to severe immune reaction. This vulnerable subset makes up about 20% of all dialysis patients.

By targeting these patients, early Invizius aims to maximize the therapy's benefits. Looking ahead, if this initial trial is successful, improving the therapy's safety, Invizius plans to conduct a larger trial. This trial, currently in design, would kick off in about a year, and involves 50 to 100 patients receiving repeated exposures of the treatment every three to six months. The goal? To prove H-Guard is both safe and highly effective in improving the health of dialysis patients. Let's hear more from Andy on what the development process has looked like for H-Guard.

Todd Poley (17:47):
I'm sure your development journey has not been exactly linear. Often with cutting edge therapies like this, you need to maneuver several challenges and plan ahead for potential roadblocks, so how has working with a contract research organization helped you stay on track in meeting your milestones?

Andy Herbert (18:04):
Yeah. I mean, the first thing that I want to make absolutely clear is that no one does this on their own. You need a team of really smart people around you. As you rightly say, the process of going from concept through to approved therapeutic or medical device is not linear. And the first thing you have to do is to nail down the basic science, and make sure you fully understand that your drug does what you think it does, but then you have to start to farm things out to different people to get different parts of expertise. There's the whole regulatory side of it, which is really important. You have to make sure that the questions that you answer for your submissions to the regulatory authorities are the questions that they're going to ask you, and so choosing the right partner in that respect is really valuable.

The next is you've got to be able to make it to the right quality and be able to prove that you're making it to the right quality. So that's a whole process development and a whole set of analytical tools that allow you to demonstrate that it is what you think it is, it's as clean as you think it is, and the quality is sufficient to put into people. And so again, we collaborated with the contract manufacturing organization to help us do that. Then, finally, there's the whole sort of preclinical and toxicological type work that needs to be done, and this obviously goes into the regulatory submission as well. In this case, how should I put this? We collaborated very, very early on with [inaudible 00:19:44], and they provided us with a lot of advice early on, before we were even anywhere near doing the experiments that we needed to do.

Then, they helped us develop a package of experiments that would suit our particular niche, because H-Guard is kind of funny. It's sort of a medical device, and it's sort of a drug, and so making sure that you've got all of the right packages, data packages in your preclinical toxicology, immunology, and all that kind of stuff is absolutely vital, and so without these various collaborators, it would've taken us an awful lot longer, because undoubtedly, we would've made more mistakes. We'd basically had to bring all of this expertise in-house, design everything, set up all the facilities, and all that kind of stuff. For anyone out there who is on this journey, I would highly recommend you choose the right partners from the beginning, and get as much advice from them as you can, because they're the experts in their field.

Todd Poley (20:45):
Yeah, and we're very grateful for Invizius to be able to partner with your program to help overcome those regulatory hurdles.

Andy Herbert (20:52):
Absolutely.

Todd Poley (20:53):
And I appreciate the sentiment of planning earlier ahead. I think that is so critical, to kind of lay that out and address it early on. I think that's a really, really great point.

Andy Herbert (21:03):
So if you think about what you're trying to do, you're trying to go to investors and the financial people with a story, and the story involves a plan. The plan means that, even before you are ready to do the experiments, you know roughly what it is you're going to be doing, roughly how long it's going to take, and roughly how much it's going to cost, and so planning that as early as possible, and then really working with the various CROs as much as you can is absolutely vital, and it really helped us a great deal.

Todd Poley (21:38):
So let's take a look at the moment that we're in now with Invizius. What are the plans for advancing H-Guard's development beyond clinical study?

Andy Herbert (21:48):
So the first thing that we have to do, obviously, is to demonstrate that H-Guard is safe, and that's the study we're in at the moment. In fact, just whilst we've been recording this, I've just got the news that we've managed to enroll our first two patients into the study, so I'm absolutely delighted to be able to share that with you.

Todd Poley (22:09):
That's fantastic.

Andy Herbert (22:10):
It's amazing. It's really amazing. And so, the next thing is we have to demonstrate that it's effective, and that involves larger trials with a longer duration with more people, and what we're trying to do is to show what the clinical benefit to that is. I'm quite confident that we can do that. It is one of the things where a lot of biotechs fail at, but I'm relatively confident that H-Guard will work in this respect, but it's all very well getting your drug or device approved. You, then, have to be able to get it out there into the markets, get doctors prescribing it and patients using it.

And so, we're now sort of thinking ahead for what our commercialization strategy is going to be, much in the same way that when we were designing the clinical trials and the manufacturing, so we've been starting to get advice from lots of the industry players in the field and find out exactly what it is they would really like to see. We talk to the doctors and find out, what would it be? What be the killer feature? I probably shouldn't use the word killer, but I guess you understand what I mean. What would be the absolute feature that would make them prescribe that to their patients? We have now a lot of good ideas, and so our subsequent trials are being designed with achieving those goals in mind. I'm not liberty to say too much more about exactly the direction that we're going down, because it's kind of commercially sensitive.

Gina Mullane (23:43):
What Andy could share with us is that Invizius is actively exploring therapies beyond their H-Guard technology. The company is focused on improving the duration of patients on peritoneal dialysis, which is generally better tolerated than hemodialysis, but often damages the vital peritoneal membrane. This damage leads to a fibrotic transition, making the membrane less effective in filtering toxins. Invizius has a couple of molecules in the final stages of preclinical lead development for this purpose.

Within a year, the company aims to initiate the process development pathway, including manufacturing and analytics. This will involve collaboration with preclinical experts to design a comprehensive package, and the potential impact of these therapies could go well beyond peritoneal dialysis. Fibrosis affects multiple medical conditions, and Andy is hopeful that the team can leverage the expertise gained in this field to expand into other fibrotic diseases. While specific molecules may vary for different indications, the underlying mechanisms and knowledge will allow Invizius to enter a broader market to address this critical therapeutic challenge. Let's hear from Andy on his hopes for these therapies moving forward.

Todd Poley (25:09):
As we come to a close, one final question for you. When you think about these patients with inflammatory fibrotic autoimmune disorders, what do you hope the future might bring for them?

Andy Herbert (25:21):
Yeah. That's a really good question. I mean, I got into this whole idea of starting to take my fundamental research to clinic, because I got slightly jaded when I was writing academic grants, saying that this can be used for that and the other, and it'll be amazing, and it'll save the world. I decided that I was going to put my money where my mouth was and actually try and do it. And so, with that in mind, you look around the space, and although there is an awful lot of innovation in the pharmaceutical and therapeutic world, generally, in the case of patients who've got kidney failure, particularly dialysis, hemodialysis, and peritoneal dialysis, the innovation has stalled.

There's been nothing to really differentiate the various different companies on this, so what I would like to say to any patients who are in this situation is that we at least are working as hard as we can to bring treatments, new treatments to you that will hopefully improve your quality of life and also extend your life as well. I guess I want to say hope is coming, and I'll certainly work my as hard as I possibly can to make that a reality, with the ultimate goal of helping as many people as possible with as many different disease conditions as we can address, but unfortunately, it's a relatively slow process.

Todd Poley (26:56):
Well, as someone who has been personally affected by the complications of dialysis through a family member, I really am excited to see the mission of Invizius and really going to be watching closely as it progresses, so thank you for that.

Andy Herbert (27:13):
Well, thank you. It's exciting times ahead, I think, in this space.

Todd Poley (27:17):
Absolutely. And thank you, Dr. Herbert for being part of Vital Science. It's really been an honor having you on the show.

Andy Herbert (27:23):
It's been my pleasure. Thank you.

Gina Mullane (27:27):
Dr. Andy Herbert is the co-founder and CTO of Invizius. Thanks for listening. Did you know that Charles River has a sister podcast, Eureka's Sounds of Science? This monthly podcast shares scientific patient and advocacy perspectives on trending issues in the drug development industry. You can subscribe to Vital Science and Sounds of Science on Apple Podcasts, Spotify, Stitcher, or wherever you get your podcasts.