Thalia Therapeutics Plc (THAT) Earnings Call Transcript & Summary

Hello, and welcome to BioBiz Buzz, the podcast where we unpack the science, strategy and stories shaping the biopharma industry. I'm your host, Mike Ward. In this episode of BioBiz Buzz, we're diving into one of the hottest frontiers in drug development, RNA-based gene silencing as a precision tool to tackle cardiovascular disease that current therapies still fail to control. Despite the widespread use of statins, a stubborn background rate of coronary heart disease, stroke and cardiac arrest still persists. It's driven in part by God-given genetic risk factors like lipoprotein(a), or Lp(a), that just can't be modified through either diet or exercise. My guest in this episode of BioBiz Buzz, David Solomon, is the CEO of Thalia Therapeutics, a recently rebranded AIM-listed company that wants to become Europe's RNA therapeutic champion. And they intend to do that by building a portfolio of siRNA and microRNA medicines. Thalia's lead vision is a once-yearly subcutaneous injection that combines gene silencing of Lp(a) with PCSK9. And the idea is to put that into a single long-acting construct, which is aiming to cover both inherited and behavior-driven cardiovascular risk in just one self-administered shot. So thank you for joining me, David.

Yes. Thank you for having me.

So when we look at the cardiovascular landscape today, what is the specific risk problem that you think current therapies aren't solving? How might gene silencing actually change that?

Yes. No, that's a fundamentally good question. We've seen the reduction of cardiovascular events, both myocardial infarction and stroke, over the last 20 years, and that's largely due to awareness of the risks and better behavior. It's also largely due to the use of statins that are widely prescribed, safe and well tolerated. But still, when you think about the wide use of statins and better communication around health, the rate of cardiovascular events when you take out cancer and accidents is still the greatest cause of morbidity and mortality globally. And so there's still an enormous need to address cardiovascular risk. And these new targets, as you mentioned, Lp(a) and PCSK9, are really the leading ones to really work on to lower that risk and ultimately have longer, better lives.

Sure. So I mean Lp(a) is the genetic risk and PCSK9 is more of a behavioral one. Why is it important to actually tackle both and why in a single therapeutic approach?

Yes. So Lp(a), as you correctly allude to, is set at birth. So the levels you have are not movable by diet or exercise or any behavior, good or bad. On the other hand, PCSK9 is a target that actually does change with behavior, whether it's eating a highly processed food diet or obesity or diabetes or lack of exercise. So addressing Lp(a) is important because even if someone is incredibly fit and exercises, they still can have a background level of cardiovascular events, both infarctions and stroke, despite good behavior. So lowering that risk by lowering Lp(a) is valuable. PCSK9, like lowering overall cholesterol levels through the statins is also very, very important and is addressable today. However, today's medicines against PCSK9 are largely antibody-based, although there is a new also gene silencing called inclisiran against PCSK9. The idea of putting the two together is a vibrant one because we want to address both the risk that is God-given, if you will, and also the risk of behavior. And if you combine the two in a single therapeutic that may be useful for once yearly dosing, I think there's a high probability that you can actually decrease the global burden of these cardiovascular events. And I think that kind of medicine will be enormously useful as a global imperative.

Yes. But many companies though are active in both Lp(a) and also PCSK9. So what is genuinely different about Thalia's tandem Lp(a)-PCSK9 construct? And what IP do you have around this?

Sure. So Lp(a) is just emerging. We were able to measure Lp(a) and quantify the risk, and we know it's linked to events, but there is no Lp(a) medicine. Novartis is probably the furthest ahead with a Phase III study called HORIZON, and that's going to read out shortly. And the whole community is paying enormous attention to the results because if targeting Lp(a) lowers the number of events, that will be a huge boom to this segment. PCSK9, as I mentioned, there are antibodies against it. But gene silencing siRNA is just beginning. So putting the two together is really another great tool in the toolbox, in the armament, if you will, on treating cardiovascular risk. And I think it's going to be one of the important tools because we don't know each individuals' both combination of genetic risk and behavioral risk. And having a combination product like that, much like in the GLP-1 space, there are, call it, GLP-1, GLP-2, GLP-1 amyloid, GLP-1 combinations that both cause weight loss but also muscle sparing. And here, by having the two most important new targets, I think we're really going to be a leading sort of medicine. You asked the question correctly about our IP. We've recently filed some IP. And I think in the future, we'll really be focusing on several things. One is how the linkers work and how we get long-acting, how we get 6 months to once yearly administration. The biggest problem with statins today is compliance. People don't take their statin every day. If you're supposed to take a statin 40 milligrams every day, the number of people that comply is only about 65%. And therefore, the risk is still there. So with once yearly injection, I think there will be the real possibility that you can have both good compliance and good response rates.

I mean, what's the mechanism that is therefore in play?

Well, for once yearly, it's obviously, as you know, with siRNA, you link the siRNA to GalNAc. And GalNAc is a sugar. It specifically targets hepatocytes, liver cells. And so you can, with a single injection today, with a liver-targeted gene silencing double-stranded RNA effect, you can get it into the liver. Anything that doesn't go into the liver is renally cleared in the urine. So net-net, once it gets into hepatocytes, liver cells, it gets into what's called the risk complex and is catalytic and it is long acting for today, 3 months. You can see that a gene-silencing medicine gets into hepatocytes and is active silencing genes up to 90% for Lp(a) for a 3-month period. By modifying the double-stranded RNA in different ways that are proprietary to us, I can't really say more, ultimately, you can get to 6 months or once yearly injections because you can have an even longer-acting catalytic activity in liver cells to silence the Lp(a) or PCSK9 gene. We also think that delivery is important. Thalia Therapeutics is the rebranded and remade name of N4 Pharma that had Nuvec, a silicon-based nanoparticle, at its core as a tool, a delivery system. And perhaps it's possible that the siRNAs against PCSK9 and Lp(a) could be inside the Nuvec nanoparticles. And by doing so, you could have different ratios perhaps of Lp(a) or PCSK9 depending on your level of risk. Do you have more genetic risk or more behavioral risk? And therefore, you could actually more tailor-make the medicines. So these medicines are already precision medicines. They bind to their target genes using a Watson-Crick base pairing. So they are specific at a sub-nanomolar level, unlike antibiotics or other medicines that are micromolar in their affinity. And so the off-target effects are zero. The side effects are near zero. And the specificity is ginormous. And then added together with combinations and once yearly administration with the correct targets, in addition to the statin world, I think you're going to see a really rational global way to reduce cardiovascular risk.

Right. You mentioned the delivery system, Nuvec, the N4 Pharma, the former name Thalia had. Is that technology still going to be important to Thalia? I mean, could you explain how you see that in what is now a therapeutic ambition?

The therapeutic ambition is clear and is most valuable. But delivery is also an enormous challenge today. I mean, today, everyone can only target rationally to liver cells using GalNAc. We think that there are many other cells and tissues that should or could be targeted with siRNA gene silencing. And Nuvec, these silicon nanoparticles, is one such way. We're currently studying Nuvec by decorating it with GalNAc to assess it getting into liver cells. But there are many other tags that you could decorate Nuvec with to address neurons, other cells of interest where diseases originate. So today's world of essentially 8 siRNA commercially available medicines is all due to GalNAc targeting liver cells, but there's a whole brave new world out there to target other cells and tissues. And we believe, in the background to our therapeutics, Nuvec could be such an important targeting system as well.

Okay. And thinking about when you're talking about Lp(a), you mentioned it is a naturally occurring molecule in the body. Presumably, it has some physiological role in the human body. So shutting it down, is that a challenge?

Well, we clearly know from plasmapheresis clinical trials done in Germany that reducing Lp(a) does reduce risk. It's been well established in that high Lp(a) cause an increased risk of events. That is extremely clear in the peer-reviewed literature. So the question really is what does Lp(a) do? And if you reduce it by 90%, is there any effect? Humans have been around for 55,000 years. But for the first 54,000 years, our existence has largely been as farmers eating a very more sporadic diet of less caloric intake, and obviously, less processed food. And Lp(a) is thought to be one of those genetic mechanisms to allow storage of fat in ways that ultimately can be used as sugars to fuel our cells when there's a lack or a paucity of important food stuff, as happened in nomadic people for most of human existence. And as we've industrialized, obviously, our diet and our exercise profile, our work life, our leisure life has changed. And Lp(a) now is only realized as really a risk factor. So of course, as there are more therapeutics and as there's more attention on these pathways, there will be more biology that's learned. But it's really thought that Lp(a) probably played an evolutionary role in terms of fat storage and then utilization ultimately as sugars to fuel our body.

All right. Yes. So interesting background there for me. So where are you in the development of this, I could call it, tandem therapy? And what does the regulatory pathway look like for a precision RNA medicine like this?

Well, so we're beginning now IND-enabling studies. And it's a very well-trodden regulatory pathway according to the FDA and other regulators. Because of the precision of siRNA and this concept of Watson-Crick base pairing to the specific gene only inside the nucleus of a hepatocyte, a liver cell, the regulators and the FDA feel comfortable that you begin with rodent studies to show essentially a dose escalation that you can suppress the gene, the target gene of interest appropriately, number one, and do it where the medicine in the animals is safe and well tolerated according to all measures of safety in animal models. Then the next layer after doing either mice or rice experiments is in nonhuman primates, cynomolgus monkeys, or macaque monkeys as they're known, and those experiments in dose escalation to really look at broad toxicology, safety and tolerability and also efficacy. And that has been well studied and well done in all of the gene-silencing siRNA medicines, double-stranded RNA, to date. And so we are beginning these IND-enabling studies now in rodents. We hope to transition by the end of '26 to our nonhuman primate studies and then, with approval of regulators, begin the path of pivotal studies. And that's the rather tried and true path in this field. But that suggests along the way that we'll also be able to perhaps gain interest from large pharma in possible licensing deals. I was earlier, as you know, the CEO of Silence Therapeutics. And against the similar kinds of approaches of siRNA, we did licensing deals with Mallinckrodt and AstraZeneca for several billion of milestone payments for each of those licensing deals and significant upfront payments. And this is a hot field where there's a lot of pharma companies that will likely be interested in this dual-acting combination medicine to reduce cardiovascular risk.

Right. You've rebranded from N4 Pharma to Thalia. And you've spoken about becoming Europe's RNA therapeutic champion. What does that ambition actually involve particularly beyond the first asset, which is the tandem molecule?

Well, as you know, and as we've disclosed as a publicly traded company, we are very enthusiastic about our dual-acting combination of Lp(a) and PCSK9 targeting with an siRNA, also using the Nuvec platform for delivery that we're advancing as well inside the new Thalia Therapeutics. But at the same time, we are always looking at new ideas to bring under the Thalia umbrella. Thalia, as you know, in modern Greek means to grow or to blossom. And there are many, many ideas both in cardiovascular medicine and oncology and also in other areas where we think that Thalia will be the rightful owner of new assets, both siRNA and microRNA, to advance the company. Obviously, we're very mindful of money. We're currently cash constrained. But on the other hand, we have essentially what we're doing well in hand with our current budget. And at the appropriate time, with the growth of Thalia, we'll raise money to address and meet that ambition. U.S. champions in gene silencing, Arrowhead, has grown from a several hundred million company to a USD 9 billion company. Dicerna was bought for over $3 billion by Novo Nordisk. Silence Therapeutics, as you know, where I was earlier CEO, is now NASDAQ-listed and doing extremely well. But there are no other companies in Europe that are uniquely focused on gene silencing, both siRNA and microRNA. And I think the ambition that we have is to be such a champion in Europe.

Yes. You mentioned Silence there, where it was originally an AIM company and then you took it to NASDAQ. Thalia is on AIM at the moment. I'm just wondering, what are you thinking about the funding and also the partnerships for Thalia moving forward?

Well, partnerships, as you mentioned, these are, in fact, key. This was the same story as at Silence. When you have partners come in, they do two things. They provide nondilutive funding, which is key for a company as it grows, but they also provide validation. And on AIM, it suggests to the AIM investors that the ideas inside the company that are being put forth are important and valuable if large pharma essentially does significant diligence, looks under the bonnet, if you will, and says these ideas are worthy. In the case of Mallinckrodt, they also invested in Silence at a 70% premium to the share price. And that drove the share price from the time I joined at 40p to around 610p in a reasonable time frame. So we think a similar model is possible for Thalia as we grow. We think our assets are important and they address real need in the marketplace. And I think that investors will appreciate that and join with us in our journey to increase value for both shareholders and for patients and their caregivers.

Yes. I'm thinking now from the patient and the health system perspective. You're developing a once yearly self-injectable RNA therapy. What will that change mean for patients and health care systems compared with today's options?

Well, first of all, obviously, there's a huge pharmacoeconomic burden to cardiovascular events. I mean, sadly, when people mid-career, midlife have an occlusive stroke, it is life-changing for them and their families both emotionally and economically, obviously. And we believe that reducing that risk is possible and will be valuable. Also, when you think about global risk, there are lots of places where people don't have access to physicians as easily as in Central London or New York City or anywhere in Europe in our advanced health systems. And we think that a once yearly administration will reduce that risk, both behavioral and genetic, in large swaths of populations in growing countries of wealth, India, China, Middle Eastern countries, where the risk is quite large of cardiovascular events. And these once yearly injections will actually really solve a significant problem and allow for better life and longer life and life with less morbidity and mortality from those risks.

Right. Now you've just been in the role of CEO at Thalia. Just you joined recently. So it's still early days. But I was thinking, if we're having this conversation in 3 years' time, what milestones are you hoping that we've seen that's going to convince you that Thalia is truly on its way to achieving that status as Europe's RNA therapeutic champion?

Sure. Well, I think if we follow the well-trodden path to advance development of our Lp(a)-PCSK9 dual-acting gene silencing medicine, either by 3 years from now, that medicine will be well partnered with a large player like a Pfizer that has deep experience in cardiovascular medicine, or we will be advancing it significantly ourselves, one of the two. But at that point, I predict we'll also have other medicines in our pipeline and our portfolio, both gene silencing and microRNA assets. And by that point, I think the markets will understand, with partnering, with advancing in the clinic, with real milestones and news flow that the company will grow in terms of its value, its market cap. And our ambition is large. I think that in 3 years' time, it's reasonable that we could be a USD 500 million to USD 1 billion -- or a GBP 1 billion company. And that ambition is not dissimilar to what happened, in fact, at Silence Therapeutics. And so we're going to follow that path. We're going to work closely with our existing shareholders. We're going to work closely with investors on AIM initially and also pharma partners to tell the story of our exciting advances. And I think, together, we'll bring all these elements of the ecosystem together to grow and, importantly, provide medicines for patients and their caregivers that we think will reduce burden of disease.

So clearly, I mean, there's some exciting milestones for us all to be looking out for. So David, thanks so much for joining me and for walking us through how Thalia is thinking about gene silencing as a way to take on some of those most stubborn cardiovascular risks that clearly current therapies just don't fully address. I mean, what you said today in summary is that we've heard about how your once yearly tandem Lp(a)-PCSK9 strategy, the IP and delivery science behind it, the regulatory and partnering path that you're targeting and also your broad ambition to build a genuine RNA therapeutics champion out of London. So thanks very much for taking the time.

Thank you so much. A pleasure to talk together, Mike.

Yes. And to our listeners, if you'd like to keep track of Thalia's progress as it moves from its pre-IND work towards the clinic, definitely keep out listening that. It's clearly going to be an interesting story. And if you enjoy these deep dives into how emerging biotechs are trying to reshape the standard of care, please follow BioBiz Buzz on your favorite podcast platform and also maybe share this episode with a colleague that you think would enjoy it. I'm Mike Ward. Thanks for listening. And I hope you'll join me next time for another conversation at the intersection of biotech innovation and business strategy. Goodbye, and keep on innovating.