Why Western pharma is sleeping on China's circular RNA revolution

0:05Dr. Lu Gao: Hello, and welcome to Beyond Biotech, the weekly podcast from La Biotech. I'm Dylan Kassane, and this is episode 209 for the podcast. RNA therapeutics has had its defining moments. Antisense oligonucleotides, PsyRNA, and then of course mRNA, which went from a niche academic curiosity to the backbone of a global vaccine program in a matter of months. The next chapter may be circular RNA. Cirq RNA is more stable than linear mRNA, longer lasting in the body and potentially re-dosable, and one company has quietly built what may be the most advanced independent circ RNA platform in the world, and with barely a single line of English language press coverage.

0:54Dr. Lu Gao: Until now. My guest today is Dr. Lu Gao, CEO of Therona Inc., a clinical stage biotech headquartered in Beijing and Shanghai. The company recently presented three posters at ASGCT in Boston, and their lead program has just entered a first in human trial. We're going to talk about the science, the clinical strategy, and why Western Pharma hasn't paid enough attention to what's being built in China. I hope you enjoy my interview with Lu Gao. Welcome to Beyond Biotech. Hello. Therona is a name that is probably a little bit unfamiliar to a lot of our listeners. Can you maybe start by telling us, well, who you are and what Therona does?

1:44Hi, I'm Lu Gao. I'm the CEO of Therona. So Therona is a clinical stage biotech company. We're specialized in circular RNA technology. And around that line, we have enabled three different clinical trials in prophylactic vaccine, therapeutic cancer vaccine, as well as in vivo CAR-T.

2:12Dr. Lu Gao: Therona was founded back in 2021 by Professor Wenxing Wei. How did you come into the picture? What drew you into the field, into the company? Yeah, that is a long story. So I was trained as a microbiologist and immunologist from University of Southern California, and I had my postdoc training as well as a research faculty experience in UCSD. And after that, I joined Roche, where I spent 12 years in infectious diseases, drug discovery, and clinical development, where we made a number of medicines and medicine candidates in clinical trials. And so I was specialized in small molecule drug discovery and development as well as RNA field.

3:13I used to work with siRNA as well as antacethic oligos. So with all this type of experience, I later worked with Hungry Pharmaceutical Company, which is the largest Chinese pharmaceutical company as a vice president, as well as CEO for two of their subsidiary companies. Over there, I had established a platform for their assay RNA technology as well as mRNA technology platform that enabled clinical development as well. So 2021, that was the time of COVID-19, the pandemic, and many companies were investing in RNA technology, especially in the linear mRNA field. so did I and I had a lot of hands-on experience with linear mRNA technology in discovery as well as manufacturer perspective so that's when the circular RNA technology draw my attention that's where I read publications as well as news regarding a few trailblazers in that field.

4:47And Therona was one of them. And actually, it happens that their investors, as well as Professor Wei, used to be my friends in the past, or collaborators in the past, so that I was aware of this technology. and back then I would say that no one had real hands-on experience in this field and it was something really amazing that can be a new thing that's better than linear mRNA and what's been published and what others announced is that it's more stable than the linear mRNA in vivo which means that it has better T-half or longer T-half that enable longer therapeutic window so that if you express protein using circular RNA, you will gain better therapeutic windows, maybe achieve better efficacy.

5:53However, this was still in the lab scale or in the beginning of a few biotechs back then. And from what the investors told me is that it's such a challenging technology. It's not straightforward. There's many things that nobody knew how to make it work, including how to translate from discovery to clinic through different steps. And also, how do you manufacture that in a qualified clinical batch? So everything was under uncertainty. But we did see a bright future in this technology. And I was intrigued and would like to take a challenge. So until 2022, I joined this company and basically started our internal research on this.

6:52So here I am. And I'm glad I'm still here.

6:57Dr. Lu Gao: things are certainly progressing since then uh you came on our radar because you presented three posters at asgct recently in boston was that sort of a big coming out moment for the company in north america yeah i guess so so we are pretty quiet as a beginning phase and during that presentation and many people feel like this is the first time they heard about it but we already had three clinical programs in circular RNA field. So it's a great opportunity that we actually can communicate to a broader audience and let people know what we could do and what circular RNA can do for people. Yeah, I guess before we jump too far into your science specifically, maybe it's worthwhile understanding a little bit of what circular RNA actually is, how it's different from the mRNA that we heard a lot about during COVID.

8:00Dr. Lu Gao: What does that circular structure mean? Why does it matter? Yeah, circular RNA is a single-stranded closed ring structure. It's just like a ring. That's why we call it circular RNA. And how does it difference from linear mRNA is that from the molecule perspective, linear mRNA is copying the endogenous mRNA, but using chemical modification, including modified nucleotides such as pseudouridin, as well as 5' cap, to enable the elongated half-life and avoiding the innate immune system from destroying it in the human body. Circular RNA, on the other hand, is using natural nucleotides. So this structure or the nature of the circular RNA could avoid the innate immune sensors in human body and make it exist for a relatively long time and enable protein expression from it.

9:24Dr. Lu Gao: So that's the main difference. Yeah, and I guess one of the big names in this space that we hear about is Orna Therapeutics, and their platform is built on this method called Pi, the permuted intron exon. Theronor has published a different approach, and we read about that in Nature Communications. Maybe you can explain what's different about how you make your circular RNA. Why does it matter that you do it differently? Sure. Yeah, the premuse intra-exome method is quite famous. Actually, the concept started in 1990s in publication that we wrote earlier before even ONA took their initiative in enhancing the efficiency.

10:14So what ONA did was they had a special design in the PIE splicing fragments. Specifically, they include additional homology arm and spacer region to facilitate the splice sites recognize each other so that splicing could happen effectively in vitro. So basically, there are a number of companies or labs are using different arrangements of the intron and axon fragments. And some of them add different type of sequence or structure in between them to enable the splicing. So what we did is we have tried quite a number of different methodologies. And one of them is splint-free enzymatic ligation method that we have applied it in our clinical products.

11:27we have manufactured using the sprint-free enzymatic method for different products. So the difference is that we split the iris, which is an internal ribosome antocyte that's responsive for protein translation initiation in vivo. So we split that and place them at two sides of the coding region of the RNA. So our linear mRNA after in vitro transcription could form a secondary structure so that the 3' and 5' will become naturally in the proximity so that we add a ligase that's very easy to ligate it together. And the beauty of this method is that we do not need any splicing, and therefore we do not generate splicing byproducts that you need to purify them away in the process.

12:35And the reaction condition is also very mild, and we generate a scarless circularity, meaning that we do not need to introduce any additional sequence in the RNA other than the iris and gene fragments. So we also invented or explored other different methods such as described in the publication last year, including complete self-splicing intro for RNA circularization. and this methodology has a different arrangement of a long fragment of yin-chong so that we don't place them in two sides, rather we put them in one side. And the advantage of this methodology is it could also use a very mild reaction condition and enable very long fragment generation of the circular RNA.

13:38Indeed, we have cloned or expressed human destrophin, which is a very large protein and with 12 ,000 Daltons nucleotide in length. So this enables the manufacture or enable expression of very long, very large therapeutic protein.

14:03Dr. Lu Gao: I guess in this space when you're trying these different methods and you're finding the ones that work, the intellectual property that you're developing really becomes everything there. How does your approach give you freedom to operate and how are you thinking about protecting about what you've built? Yeah, intellectual property that is the most fundamental area that is important for us so the splint-free enzymatic method was originally invented in Professor Wei's lab so that was the first thing that I recognized from all his inventions as the most valuable part. And we had exclusive license from Peking University to Serona so that we could use this methodology for our platform products.

15:05So this patent has been granted in major markets so that we're quite clean in terms of protection in this methodology. And all the other platforms or methodology that we have invented, we also filed PCT patent applications worldwide, both for the methodology and for the RNA sequence themselves for each individual product.

15:42Dr. Lu Gao: Let's talk a little bit about the lead program that you've got there in CAR-T. It's TI0032. The basic concept, at least as I understand it, is you're programming a patient's own T cells in the body without taking them out. And that seems pretty exciting. Can you actually walk us through what it actually does when it enters the patient? What's going on? Sure. So from the product perspective, we deliver the circular RNA to the human body using a lipid nony particle. And on top of the lipid non-A particle, we coded with antibody fragment that recognized human T cells specifically. So that antibody will drive the lipid particle and the circular RNA into T cells, and the RNA will be released into the cells and translated to CAR molecules, and that will be presented on the surface of the T cell.

16:56So that includes antibody fragment recognizing the target cell, which in this case is B cell. So that the T cell becomes activated and recognize B cell and therefore kill the B cells in the human body. So this will be useful for a number of different indications where you have abnormal B cells. and that includes autoimmune diseases as well as some type of blood cancers.

17:29Dr. Lu Gao: That's what interests me really because you're developing this right now for autoimmune disease rather than strictly for oncology. Why are you targeting autoimmune? We are targeting autoimmune diseases as our primary indications because number one is that we do see the huge amount of need in autoimmune diseases. There are lots of complicated indications within autoimmune disease. Those are driven by B-cell abnormality, and there's no very effective solutions, or at least the patients need to be dosed with all the standard of care for the rest of their life and could only achieve certain level of control of the disease progression.

18:30So luckily, our in vivo CAR T could target those B cells in such indication. And the reason that since recent years we have observed several autologous CAR-T has been applied in the exploratory early clinical trials and demonstrated a very promising result. So from that perspective, we understand at least there has been proof of concept using autologous CAR-T. And therefore, if we replace autologous CAR-T with our in vivo CAR-T, we could achieve a similar effect, but at better convenience without nipple depletion.

19:17Dr. Lu Gao: That preclinical data, the data you produced at ASGCT, that included complete B-cell depletion in non-human primates. I mean, you sound like it's making you pretty confident, that data, as you move forward and you start to move towards in-human studies. Yes, we are quite confident. And the confidence came from three different layers. First of all, we have observed that in resting human T cells, in the resting primary T cells, we could achieve very high level of transfection and expression for longer than two weeks, which is quite long. And in the humanized mouse model, we could observe complete B cell depletion at very low dose level.

20:14And also we observed that in the non-human primates, we could also observe complete B cell depletion in tissues at relatively low dose level. So that brought us the confidence moving forward into clinical trials. And we currently are having ongoing IIT, which is an investigatory initiative trial in autoimmune disease patients.

20:46Dr. Lu Gao: One of the big limitations of conventional CAR-T is that it's one shot, it's highly personalized, and the costs are enormous, the complexity is enormous. We ran an article just a couple of weeks ago about the most expensive drugs on the market and it's no surprise that these really personalized one-shot therapies are right up there. You're positioning your product though as something that's re-dosable, that's off the shelf. What does that mean for patients? What does it mean for payers?

21:21out of the shelf and reducible it means that the patient could reach to the therapy much earlier than the autologous CAR T without a tedious CMC production process reaching to a therapy earlier yearly means better efficacy or better outcome especially for cancer patients. And it also means that we are manufacturing such product as a very low fraction of the cost of autologous CAR-T, which make it very affordable, both for the patients, also affordable for pharmaceutical companies because we need to manufacture them and run clinical trials. So at the end, I think that will solve the issue that not many patients could afford autologous CAR-T, and not many pharmaceutical companies could produce enough doses for all the patients out there.

22:35And we consider that will bring the therapy to more patients who need it.

22:43Dr. Lu Gao: you're at the moment uh on track for quarter four uh ind filing both in the u.s and in china um you know running a parallel regulatory process on two continents in two big markets it's not simple you know what does it mean for you on the inside what what does that process look like how much stress are you and the team under

23:08Yes, we are on track for parallel IMD filing in U.S. and China because those are the two major markets where patients are. And based on the past regulatory interactions, we already gained some insights on how does the package shell look like. and we have a fair level of confidence, and this will run smoothly. We do observe there are differences in the regulation as well as medical practices in these two continents, And therefore, we will adopt our clinical trial plan to be suitable for the trials in both regions. We will also adopt some of our CMC procedures, especially the QC methodology, to cover the requirements in both continents.

24:15and we are comfortable at this level and with reasonable stress but this has been planned out and we do see that with our past experience in terms of regulatory interaction this will be on track

24:36Dr. Lu Gao: You know when I was preparing for a conversation today the number that struck out to me was that since 2021, there's been nearly$7 billion in deals in this in vivo cell engineering space, no deals with a Chinese company. Why do you think that is? Yeah, that's a good question. I always wonder in my head as well. Yeah, especially in this CAR-T field and in vivo CAR-T field, we did observe there are quite a few deals already. However, there hasn't been a deal with Chinese Belltech or pharmaceutical company so far. And we hope that we will become one of them or one of the first in this area. I guess I do see that there might be some difference in dealing with American biotech versus dealing with Chinese biotech.

25:44First of all, we could see there could be communication gaps and awareness gaps. I do observe that big global pharmaceutical companies are investing heavily in the last two years in China and put their resource in terms of partnering in the local force to be able to interact with Chinese biotechs. And this is very important for them because they need to gain first-handed information and more thorough communications with Chinese biotech to understand each different project's problem comes. and when such similar deals happen in US, such interaction could be much simplified and hopefully that will change the trend in the next couple of years.

26:50Dr. Lu Gao: There's sometimes an information mismatch there. There's the communication issues that you talked about. There's also a real geopolitical backdrop to that as well because there's biosecurity legislation, maybe some additional scrutiny of Chinese biotech, the Biosecure Act, all the discussions around there. Does it make it more complicated for you to pitch yourselves to Western partners? And how are you navigating all of that? Yeah, it does cause some difficulties. And so first of all, we do observe in certain areas especially within the CGT field, certain technology has been observed from both governments as top secret, and they probably have certain hesitation in promoting deals between these two countries.

27:51So we do also observe that from a business acquisition perspective, It's not a very simple transaction to do the acquisition between the two continents. So in our VD strategy, we are seeking for licensing out and collaboration from discovery and clinical perspective instead of setting acquisition as our primary goal. And with a relatively clean project, well-defined project or asset, such concern probably will be at much lower level.

28:41Dr. Lu Gao: Beyond this regulatory and geopolitical environment, though, are there still things that Western pharma companies might just misunderstand about what's coming out of Chinese biotech? Is there anything that they still just get wrong? I think they're probably getting much better understanding year by year, but there still might be gaps in terms of how do you identify a well-differentiated asset from the very crowded competitive landscape. We do observe in China, biotech, sometimes you see many similar sets at similar stage. We do observe this from our own information channel. And we could tell from the fine details that they're actually very different from each other and may not even be at the same stage.

29:51But from an outsider's perspective, they look quite similar and at the same stage. So this is probably where misunderstanding happens. And more communication is needed to really distinguish one from another.

30:12Dr. Lu Gao: Now, you've already raised more than$70 million to get here. as you're thinking about the next phases of financing is a western partnership part of that picture I know you just mentioned potentially licensing in the future but when it comes to fundraising will you be looking to the west as well yes actually we are a joint venture and we welcome investors from both China and US or other parts of the world And we also look forward to potential BD with our lead assets. And we are welcoming a number of different type of business model of collaboration so that not only our TI-0033 could be within the scope of discussion, our other assets could also become part of the licensing deal.

31:11And I hope that will give us not only the cash flow that we are needing, it also will speed up the global clinical development of our best assets.

31:27Dr. Lu Gao: let's uh look a little bit forward if your jewel ind for the lead asset ti0032 if it clears in quarter four this year and you start enrolling in the u.s what is that going to mean to to you what's it going to mean to the company uh it means a lot i i think uh in from from the company perspective i would say that it's a big step of our leading project to generate human data in the U.S. That will definitely speed up the global development of this asset. And if that really happens, I think we're very confident that we're going to see promising data coming out of it because we're already running the IIT in China and a much faster approval concept.

32:23and those regimen, that's the foreseeable future. And from my personal perspective, I think circular RNA is a technology that I have invested several years in, and that will be a big step as a big achievement.

32:43Dr. Lu Gao: So where do you actually see Therona going in the next five years? Are you going to stay this circular RNA platform company, or are you going to start defining yourselves more as, working in a specific therapeutic area, autoimmune or oncology, what's it going to look like?

33:02I think Therona will stay as a platform company in five years. And I do see that the fundamental technology we have built in Circular RNA could branch out the different projects for different potential partners. And that probably is not restricted to certain disease area. From internal project perspective, I would like to stay within autoimmune diseases as well as oncology. But all the other fields, including metabolic disease and any field with medical needs, could be our future. but that may be within a broader network in the form of a collaboration.

33:58Dr. Lu Gao: For the researchers, for the investors and maybe even for these potential partners that are listening today, what's the one thing you want them to understand about Therona that they probably won't find in a press release or it's not going to be front page on the website?

34:16So first of all, our technology is very unique, has been clinically validated, and we have the manufacturing experience under GMT regulation so that we could bring multiple projects to human with the right collaboration. So this is not at a life scale or as a first proof of concept scale. So we did have clinical experience of circular RA project in humans three times already. And we could utilize that experience to accelerate future development.

35:04Dr. Lu Gao: and I guess finally if people want to follow along with your progress they want to keep track of what happens with the IND is there a rate a way that they can reach out to you if they want to talk or a place they can go for information sure they could go to our website at www.derona.com and they could write an email to info at derona.com any any business ideas for collaboration is welcome. Dr. Gow, thanks for joining us today on Beyond Biotech. Thank you, Darren. That's it for this episode. Don't forget to check out all the latest news and analysis at labiotech.eu. I hope wherever you are in the world, you have a great week ahead.

35:52Dr. Lu Gao: Thanks for listening, and I hope you'll join us again next time for another Beyond Biotech.

36:02Thank you.