The Silent Killer: The sci-fi episode

Wearable kidneys. Organs on a chip. Xenotransplantation. The future is here.

But is that the future people in biotech are truly looking to? Because the future that Certa Therapeutics CEO Darren Kelly is looking to is much less 1980s sci-fi and more... Apple watch.

And in a future where the numbers point to a rise in lifestyle diseases thanks to diet and a lack of exercise, climate change is an added risk that few are yet factoring in. Professor Meg Jardine, the head of University of Sydney's Clinical Trials Centre, explains where the risks are.  

Produced by Rachel Williamson and Charis Palmer. Music and effect credits to Ziso, Inspector J, Seth Parson and Boom Library.

Chapters

• 2:04 Certa Therapeutics founder and CEO Professor Darren Kelly
• 16:48 University of Sydney Clinical Trials Centre director Professor Meg Jardine

Transcript

Rachel Williamson: 0:01

A kidney in a backpack. Just imagine it. Or an organ on a chip. The future is coming people. Are you ready for it? I'm Rachel Williamson, and this is Phase III. 

I think that an organoid, a mini organ made out of stem cells, is amazing and wonderful. But it turns out my wonder points more to a heavy diet of 1980s science fiction then modern technology. Because organoids are so five years ago. PYC therapeutics from episode two is basing its kidney clinical trial strategy on data partly gleaned from an organoid. Organs on a chip, specifically a mini mock-up of the glomerulus or the tiny blood vessels that make up a kidney, they're here too. Heck even wearable kidneys aren't sci-fi anymore. Last year AWAK Technologies and Singapore General Hospital started a pre-Phase III clinical trial testing just that. This year, the first living human received a kidney from a gene-edited pig. They died two months later, but the scientific achievement still stands. 

So it takes more than 1980 sci-fi to get a kidney specialist's attention. The blue sky dreams of biotech executives in this field is... no disease. A world where our bodies are overseen by inconspicuous devices that monitor and adjust before damage happens. Where medical professionals will be able to tweak medications or supplements from afar. This is definitely worthy of a sci-fi novel. And probably harder than making an artificial kidney. But with Certa Therapeutics CEO and founder, professor Darren Kelly, we started our conversation a little closer to the present day.

Rachel Williamson: 2:05

Darren, thanks for joining us.

Darren Kelly: 2:08

Good to join you, Rachel. I'm looking forward to our discussion.

Rachel Williamson: 2:12

As am I. Let's start with some exciting upcoming therapies. I've been very interested in semaglutide and the GLP-1s, which look like they could be a kind of wonder drug for diabetic patients who have kidney disease, as well as weight loss. There are all of the SGLT2 kidney drugs, which work a little differently to lower blood sugars and, like the Novo Nordisk flow trial for semaglutide last year, all of these closed early too. Then we've got innovations in the likes of non-steroidal mineralocorticoid receptor antagonists, which crucially don't suppress the immune system, which many kidney drugs do. And there's some other really interesting therapies coming through as well. So, Darren, what in your opinion, can we expect from novel therapies in the future?

Darren Kelly: 3:03

Look, I think you're right. I think the GLP-1s are going to be groundbreaking and they're going to have a huge impact in terms of mortality. And it's not just in, in patients with chronic kidney disease, but metabolic disease in general is a, is a massive problem as you know. And so, you know, they, they are likely going to have a huge impact in this, this, field, but we've got to look at disease.

Rachel Williamson: 3:23

Can I just, um, get you to expand on that just a little bit more.

Darren Kelly: 3:27

Um, it's, it's, it's around metabolic disease and, and that glucose control. Um, we know that the Western world is generally overweight. Uh, there's lots of, metabolic diseases, whether it's diabetes, whether it's liver disease, and so the data is already shows that those drugs are going to have a huge benefit in society. But that's not going to cure everything. It's one part of a, a, a big problem. It's going to be, you know, multiple pills, multiple tablets, multiple targets that really address things in the future. I think GLP is one angle. You talked about endothelin receptor antagonists. That's another angle. but yeah, I think you're right. I think GLP is going to be a groundbreaking drug of the 2020s and we're already seeing that.

Rachel Williamson: 4:15

Chronic kidney disease, it really is going to be one of these illnesses which require a huge number of different specialties coming together to do the work. And this in itself is something that we've talked about for many years, everyone working together. But, would it be true that kidney disease is one of the first indications where this is going to have to happen?

Darren Kelly: 4:42

I think you're right. I think, um, Kidney disease is a very complex disease. People are always trying to look at one tablet to cure kidney disease, and we know that's not going to be the case. It's going to be a combination between, you know, artificial intelligence, wearables, multiple drugs, precision medicine, you know, a whole range of different areas to get a group of people together, you know, from mathematicians to biologists to chemists,

Rachel Williamson: 5:08

Mathematicians, that's an interesting. Where do you see them fitting into the...?

Darren Kelly: 5:12

Well, the artificial intelligence, the bioinformatics, you know, if you're going to interpret masses of data, you need mathematicians and, and this is where it does become a diverse field because you bring in other specialties. It's not just biologists and chemists, pharmacologists and people that make drugs. It's mathematicians and they're going to play an important role in helping us understand how we interpret this data and then apply it to, to patient benefit.

Rachel Williamson: 5:40

How do Certa's kidney therapies fit into that vision of the future? Because if it works, and I would always say if when you're still, when a drug hasn't made it all the way through commercialisation yet, if it works for chronic kidney disease and focal segmental glomerulosclerosis, that's FSGS, a rare disease, how big a step change would it be given the therapies already on the market and those in research and in trials now?

Darren Kelly: 6:11

Everyone's looking for the key switch, you know, the light switch that turns off all the lights. We've identified a novel target. So GPR 68 is a master regulator of fibrosis. And this is a surveillance mechanism, uh, basically detects when your kidney or any other organ undergoes damage from hypoxia, so a lack of oxygen or acidosis or mechanical strain, and then it switches on this receptor to try and help the organ out. But if you maintain that receptor's activation, then it causes inflammation and fibrosis. Fibrotic diseases basically are what cause our organs to fail, in particular the kidney and heart, but they're associated with about 45% of deaths. And so targeting GPR 68 is a real advancement in terms of new therapies in this space and preventing end organ failure. The kidney is the perfect example of why people end up on dialysis because of fibrosis. So, yeah, we've basically identified a master regulator of fibrosis which is going to be critical to preventing these diseases and end organ failure.

Rachel Williamson: 7:19

So you think you have identified the master switch where others may not have?

Darren Kelly: 7:24

Yeah, it's, it, there could be multiple master switches, but we already know from our molecular signatures... so this is where the mathematicians come in and working with Professor Matthias Kretzler's group in Ann Arbor in the United States. We've identified a signature, so it's like a key that looks at all the different pathways that get changed in the kidney as you get inflammation and fibrosis. Uh, and we know that our drug will block or modulate those pathways in the right direction. Uh, and so that signature then gives us a key to understanding how we can prevent diseases with different drugs and the data we've got at the moment is, is really quite compelling in this space and it really does give us a lot of confidence that we can have some benefit in patients with it chronic kidney disease.

Rachel Williamson: 8:12

Let's talk about some of the, what I would call really out there stuff that's happening, like stem cell therapies, wearable kidneys, xenotransplantation. Those last two for me are just crazy that we have technology to do this now. What do you actually think about these technologies? Do they have legs?

Darren Kelly: 8:35

Um, look, Xenotransplantation has been in development for many years, and similarly stem cells. You know, eventually, we're making incremental steps forward there in science and usually what happens is that you, um, you put money into something and you learn more about it. So, you know, they're still a long way off, particularly Xenotransplantation. You know, pig kidneys getting close to being able to be potentially used, wearable kidneys, people have been working on that for a long time. I think there's huge potential there. And, and same for stem cells. 

I think the area that's, that's blue sky is, is really back to the mathematicians and the artificial intelligence, the precision medicine and the wearables where we've each got a watch on and that's measuring what's happening to our body, live, actively. And you can turn up to your GP and they go, okay, so you need an increase in your angiotensin type one receptor blocker and that will stabilise your blood pressure. You need a change in this dose and a change in that dose. That combination of, of wearables with artificial intelligence and precision medicine will help us, preserve organ function, help us be more healthy. But ultimately, it's about prevention. So you want to stop people having diseases. Uh, so I think that's the blue sky area. I think it's, it's the combination of all those different areas being brought together to improve health

Rachel Williamson: 10:03

On a scale of, let's say one 10, where do you think we are in the journey towards that blue sky future? 

Darren Kelly: 10:13

Realistically, I'd say we're a two or a three, but you know, things change very quickly. Uh, there's a lot of money, Google analytics and artificial intelligence, being poured into these areas that, um, you know, eventually we're going to see, you know, huge changes in, in medicine and the way it's done, you know, old fashioned pharmacology has been fantastic, uh, for the past hundred years, but the next hundred years we're about to see, a massive change in this space.

Rachel Williamson: 10:40

You think that people generally will have the trust in those organisations that you mentioned, the Googles and so on, to allow that level of, uh, monitoring into their lives to do that prevention? Um, people will allow it obviously, uh, after they have found out they have a disease, but what about beforehand?

Darren Kelly: 11:07

Well, you'll have your trailblazers. You'll have your early adopters. Uh, I'll certainly pick up a, a watch and, and, happily have things monitored, as they happen. And I do. Yeah, absolutely. Um, so, you know, I think you'll have the early adopters that will set the scene. And then when people start living to a hundred and having a great life, the others will go, well, hey, I'm not missing out on that. And people will jump on board. So I think there will be trust issues you know, that we're selling our information to Google and Microsoft and whoever else, whatever other companies are maintaining all these databases of information. But ultimately it is the way things are going.

Rachel Williamson: 11:48

Yeah. Health regulation, health data regulation is going need catch up a lot with that, isn't it? Now a lot of this comes down to early diagnostics. And while we've seen a lot of really exciting therapies in the market now and on the horizon, diagnostics is lagging. What do you expect to happen in this area in the future? And are we going see activity and investment in diagnostics catch up? Or are companies still going to focus on the problem that we see now, which is the disease when it is diagnosed, which tends to be late stage.

Darren Kelly: 12:27

You're right. Diagnostics are lagging behind and it's a business model issue. The return on investment is just not there with diagnostics. If you identify someone that has chronic kidney disease in the first six months and they don't really have any significant clinical outcomes for ten years, that's 10 years earlier you've picked something up, which is great in terms of potential treatments. Um, but there's also a huge cost and burden associated with that as well and what you do with that information. Uh, you need something to treat the patients with at that time rather than just say, hey, you've got kidney disease and in 10 years time, uh, you're going to have declining kidney function and in 20 years time you might have kidney failure. Um, so I think investment in the diagnostic space will improve, but it's still a return on investment issue ultimately. And, you know, we end up going for the path of least resistance in an area where it's risky. Everything we do is risky and the chance of success is quite low.

Rachel Williamson: 13:35

Yeah, and once you have those longevity trailblazers who want to know what's happening in their body in their forties, their fifties, I guess those sorts diagnostics will start come into their own or at least have some kind payback. Are you seeing that now though? Are you seeing any green, green shoots around that prevention theme, particularly from government?

Darren Kelly: 14:00

Yeah, look, it is really hope and expectation. There's not a lot of investment in the early stage diagnostics for the reasons I mentioned before. Except in the sort of the technology space, in the wearables and those things, you know, slowly making incremental changes. You'll be able to...

Rachel Williamson: 14:20

In the technology space?

Darren Kelly: 14:23

Well, it probably is, you know, just the early data around glucose control. You know, nowadays that you can control glucose quite accurately in patients with Type 1 diabetes and if you can monitor that glucose and maintain a physiological level that's stable, um, then you've got, better outcomes, in 20 years time because you are really preventing the disease early on.

Rachel Williamson: 14:52

And if you can keep that under control, then that's a huge swathe of kidney disease that never happens.

Darren Kelly: 14:58

Well, hopefully that's the case, exactly. And if it does happen, maybe you're too, too late anyway, and, it is not as significant when you're 90 years old.

Rachel Williamson: 15:08

That was Certa Therapeutics founder and CEO professor Darren Kelly. He wants to see a future where disease is prevented. But the odds are not in our favour for that to happen.

Charis Palmer: 15:25

Hi there, I'm Charis Palmer, producer of Phase III. When Rachel and I set about building a new podcast for life science leaders, scientists, and long suffering biotech investors, we looked at what was missing in this space. We believe Phase III serves an unmet need for in-depth conversations in a world where nuance matters and AI-written investment articles simply won't cut it. If you agree, please follow us and sign up to our newsletter via LinkedIn, pledge financial support at phase3.buzzsprout.com and rate and review the podcast on the podcast platform you use, to help bring it to the attention of others. Now, back to the show.

Rachel Williamson: 16:03

You can dispute the eight glasses of water a day recommendation for kidney health. But what it does do is pointed to the underlying need of our bodies and to that organ in particular for hydration. We are entering a world with three degrees of warming is not unlikely anymore. It's going to get much hotter and might get much drier too. Both of these are bad news for kidney disease. 

I went back to Professor Meg Jardine from the University of Sydney Clinical Trial Centre to ask her about what she believes the future holds for kidney disease, kidney disease drugs, and the size of the problem. 

Putting your futurist hat on, where are the treatments, at least, and diagnostics, if you can speak about that, going to go in the next decade? And then after that, where do you see the future going for this particular indication

Meg Jardine: 17:06

That's a great question. Look, I think there are two, two paths for those big, broad, blockbuster drugs. I think we really need to get better at delivery. and keeping people on the drugs so that they continue to get the benefits. The health economics is being done on a number of them and, it's going to save the community if we do that and the taxpayer, let alone improve outcomes. So I think for many, it'll be learning how to use those ones that we're already learning about more effectively, um, how we learn to use them together, and, and delivery.

Rachel Williamson: 17:43

As a quick reminder to our listeners. The big blockbuster kidney disease drugs are Boehringer Ingelheim's Jardiance, Caliditas Therapeutics' TARPEYO, AstraZeneca's Farxiga and Bayer's Kerendia. And even semaglutide, the diabetes drug that is now beloved as a weight loss tool. 

Meg these are the big drugs that are looking after chronic kidney disease, diabetic kidney disease, the really common forms. But what about drugs for rarer forms of kidney disease?

Meg Jardine: 18:18

I think the best future would be is if we get on top of precision medicine. And that means, you know, treating people for as long as they get benefit and no more, treating the right molecule with the right dose and everything else. Whether or not that happens is a bit harder to, uh, to see. I think there'll be two fundamental things that are needed. One is we'll need markers of precision medicine and, there's been some good work done but we need, we need to go further. So that we can, we can tell when someone's responding, what they will respond to and so forth. The second thing we need is the right incentives again. Uh, one of the appeals of precision medicine is that you don't over treat, um, that you know when to treat and you know, and you can then, you know, you know when not to treat. Okay. And we need to make sure we've got a health system that rewards that behaviour, and that, that part will be maybe trickier, but if we get that right, then we're going to be better for the, the patients, better for the health service, and better for the planet.

Rachel Williamson: 19:21

Can we talk about some of the risk factors for this cohort of diseases going into the future? And now I'm particularly talking about climate change, dehydration and lower blood flow to the kidneys and heat is obviously a risk for anyone who has any form of kidney disease. There was a study in the Lancet last year, which forecast into the future, the annual loss of years of healthy life as temperatures rise due to climate change. And those were researchers from the Universities of Adelaide and Sydney, and they forecast that the number of people with kidney disease will at worst double by 2030 and triple by 2050 if humans, a) don't adapt to higher temperatures and b) don't try to reduce emissions so that temperature rise isn't, um, as drastic. In a hotter world, which some researchers in Australia say is going to hit two degrees by 2030, what are your expectations of the burden of kidney disease? And what are the realities that medical professionals and researchers like yourself are going to be faced with?

Meg Jardine: 20:31

Kidney disease is going to keep advancing, um, it's, we've got all these wonderful treatments, but it will take a while to turn that ship around if nothing else changes. So we know, I think we can lock in some advancement in kidney disease. Climate change is another stress on top of that. But, um, there, uh, some people are more vulnerable than others, but in particular people in the hottest parts of the world and people who, um, agricultural workers, people who work outside are already vulnerable. There's a condition called CKDU, chronic kidney disease of unknown origin, and that's, there are pockets of that around the world. But what unites those, um, those pockets are that they are agricultural workers. They tend to be men and they work in hot climates. Um, they are already vulnerable to heating environments and that, that is just going to get worse. that's an obvious example, but beyond that, there are also people living in, in urban communities, uh, where climate change is, is likely to affect physical activity, where people work, how they move around, exercises, potentially what they eat, and none of those things are likely to favour, healthy lifestyles.

Rachel Williamson: 21:47

Are you looking at any other external risks like that, which you're just thinking this is going to be another thing on top of all the things that we're dealing with with kidney disease now?

Meg Jardine: 21:59

The water quality is a big one, that's a risk both for, for people with chronic kidney disease, but it's also a risk for the delivery of dialysis services. Um, it's certainly a risk for, for many types of infections. A huge threat is, uh, the progression of, urban lifestyles with low levels of activity, highly processed foods, don't see signs of those reversing. And, you know, I suppose there's a climate change factor there as well. As agricultural productivity gets affected, we might be, you know, pushed even more into highly processed foods, um, and we know that those foods with high salts, and, you know, highly concentrated, um, carbohydrates and fats, et cetera, are, are not good for, for health for any of those chronic diseases.

Rachel Williamson: 22:50

Let's talk about AI. It's on everyone's lips right now as in healthcare, as in everywhere else, but we've been sold dreams before about how X way of doing things or Y software is going to change healthcare for the better, particularly during COVID during the pandemic. There are a lot of different things that people were saying "this is going to be amazing", and yet that mini glomerulus on a chip, just to take an example, really has opened the doors to new innovations. So what tech do you see in future making a really big impact on therapeutics and on diagnostics?

Meg Jardine: 23:30

Look, I think AI does have great promise, if used well, like any tool. I think ways to better design drugs for targets which potentially with AI we can do, we can, you know, model, uh, proteins and, and design something to, uh, um, at least conceptually design something to attack that target. And so we could be much more precise.

Rachel Williamson: 23:53

I guess, especially given that there are so many different, you know, you've got your heart issues, you've also got some gut issues going in there. And so you can use the hive mind of AI to sort that out.

Meg Jardine: 24:04

Yes. Um, for that design, what that's going to rely on though is not a tech issue. What it's gonna rely on is access to a lot of, um, biological samples. There are biological samples stored separately around the world, and there are many missed opportunities to collect biological samples, particularly the rare diseases, but you know, even the common diseases. Uh, and then those samples that we've got tend to stay in separate repositories. If there was a way to combine those, you know, into a massive repository and put AI to work -- AI can only work as, any tool can only work as well as, as, um, the material it's presented with -- so potentially there could be a huge yield there if we better consolidated the biosamples we had, had better sharing, um, and then used high tech, um, with it.

Rachel Williamson: 24:56

Oh, yes. That sounds like you're asking the children to share. How would you as a public health researcher, Meg, go about that?

Meg Jardine: 25:05

Industry collects a lot of samples. If there were things that incentivated industry to maybe fund a common pool and then get access to buyer banks, so that they could develop, the targets that they were interested in, but that there was a, a large common, resource that everyone, could access. That, I think in the end, does require some public investment. and so, you know, a political decision to do that.

Rachel Williamson: 25:33

So the COVID pandemic really showed us what governments research and industry could do with the right incentives. But do you think it might be possible to keep any of those gains? Are there any processes in place that you would push hard to keep or to bring into Australia if it was demonstrated in another country?

Meg Jardine: 25:52

One of the ways we could transform health is by better integrating research and health delivery. Essentially, they still run as two different systems that are cordial towards each other, but they're two different systems. Whereas embedding research into health gives you better quality outcomes, um, and it also means the research is informed by the setting it's, it's generated in. Um, we had an inkling of that in COVID, you look at where success hit and where it didn't the best example that most people talk about is the recovery trial in the UK. And I think partly it was, you know, it was a really clever, simple design. But I think a big secret of its success is it was embedded in the health system, and that was because there was already infrastructure, that the UK had set up to embed research into, um, into healthcare. So I think that, that's been a really clear example of, of why we should embed research into clinical systems, apart from the obvious efficiencies of, you know, not duplicating systems. If I was, um, Prime Minister for a day, I think that's what I would be doing.

Rachel Williamson: 27:07

Prevention of disease and fixing the health and medical research sectors. They're not small dreams and they're not the stuff science fiction is built on. But these blue sky visions of the future for kidney disease are what could make an actual difference. Changes to the way clinical trials are run gave biotechs and their investors an opening to start working on kidney diseases. The results are appearing today in the form of drugs that treat the worst stages of the disease. They're coming alongside other tech innovations, like the glomerulus on a chip which are accelerating research that lead to treatments. This corner of life sciences is changing at monthly. So what is science fiction and kidney disease today, could be the future of tomorrow.