Rewriting the rules of genetic medicine with tRNA therapeutics

0:05Hello, and welcome to Beyond Biotech, the weekly podcast from La Biotech. I'm Dylan Kassane and this is episode 214 for the podcast. Most genetic medicines are built to treat one gene, one mutation, one disease at a time. That's true even for the newest modalities, gene therapy, gene editing, mRNA, each still has to be engineered disease by disease. Alterna is testing a different idea, that the real target isn't the gene, but the process of translation itself, where genetic instructions become protein. The company's lead approach focuses on nonsense mutations, a shared error responsible for roughly a tenth of all genetic disease diagnoses, and asks whether a single engineered molecule could address it across many conditions at once.

0:58My guest today is Dr. Nerissa Crea, Chief Medical Officer of Alterna. Nerissa brings two decades of rare disease drug development experience, including CMO roles at Entretter Therapeutics, Tiberio Therapeutics, and Avrabio, to the task of turning that platform thesis into an actual clinical program. We'll talk translation, trial design, and what it takes to bring the first engineered tRNA therapy into the clinic. But first, a word from our friends at Inside Biotech. hi everyone my name is karish manchaghani and i am the co-host of inside biotech the official podcast of biotech connection los angeles or bcla for those who may not know bcla is a non-profit organization dedicated to inspiring educating and connecting emerging scientists students and entrepreneurs to help grow and diversify the biotech ecosystem in los angeles on inside biotech we invite you to get a behind-the-scenes look at one of the fastest-growing biotech hubs in the country.

2:03Each month, we sit down with scientists, founders, investors, and industry leaders to talk about the cutting-edge science inside their companies and the personal journeys that brought them there. From breakthrough therapeutics and AI in healthcare to career transitions beyond academia, we explore how science, business, and storytelling intersect to shape the future of biotech in SoCal. If you're a student exploring careers in STEM, a young professional navigating the industry, or simply curious about the people driving innovation, this podcast is for you. Search Inside Biotech wherever you get your podcasts and give us a listen.

2:38We'd love to have you join us.

2:45Nerissa, welcome to Beyond Biotech. Thank you, Dylan. Nerissa, you've held CML roles at Entrata Therapeutics, Tiberia Therapeutics, Avrobio, and you've worked across gene therapy, neuroendocrine disease, metabolic conditions. What drew you to Alterna, this platform, especially when it's so early in its clinical life? Sure. So two things. One, the science, very interesting science, and we'll get into that in much more detail today, I'm sure. The other piece is the patients. So working in rare disease throughout my career, I've had many opportunities to sit in front of patients, mothers, fathers, family members, and people are always looking for something for their child or their loved one.

3:39And as we think about rare disease drug development, Alterna and the tRNA platform offer something for the more and more rare diseases that oftentimes we haven't been able to access in typical development programs. So looking at those two together, I was very intrigued and very interested in participating in what Alterna was doing. Because you were a pediatric endocrinologist by training, you know, having these families coming to you when they have something very specific, a very rare disease wrong with their child. And now we're talking about rolling out a therapy that's for potentially dozens of rare diseases at the same time.

4:23You know, it must be somewhat really gratifying to be pushing towards that position where you could answer all of those parents, all of those families. Yes. So, you know, my background as a pediatric endocrinologist, I think, was a great setup for ultimately transitioning my career into industry as well as into rare disease. Many of the diseases we see as pediatric endocrinologists are rare diseases. And so you're right. I mean, working across a 20 year career and again, tying back to those questions of what about my child? What about my loved one? This was just such an interesting opportunity.

5:05and you know it's remains something that we have to think very carefully about how we're going to execute on the tRNA platform and what diseases make sense to combine in trials and such but I do think it's a really interesting opportunity to offer again those more and more rare diseases something in clinical trials and ultimately hopefully a registered drug. These sort of decisions and strategies that you're talking about. As a CMO, you're sitting right at that point where you're having to translate the science that you have in the lab into a clinical strategy, a regulatory strategy. For you, how do you manage this process of handing off from a platform thesis to an actual protocol design, something that might lead to that registered drug?

5:58Yeah. So, I mean, that's one of the most fun things about working in this industry. You know, having been able to work in those early phase companies where you're doing exactly as you described, taking platforms, taking early research information and thinking about how are we going to bring this to the clinic? And so oftentimes I liken it to putting a puzzle together. So you're thinking about all of these pieces that ultimately have to line up and fit together to get to successful clinical trials, successful registration. And so it really is looking at cross-functional teams, cross-functional data, and considering how are we going to put these all together?

6:50You know, for us at Alterna, this first program, AP003, which is a tRNA therapy encapsulated in a lipid nanoparticle, you know, we have been thinking about animal models. We've been thinking about manufacturing the drug. And now ultimately thinking about, okay, what does the clinical development plan look like? from phase one, healthy volunteer trial, all the way through. What we are hoping to do is basket trial approaches, and we can get into more detail on those. Yeah, I'm going to come to the basket trials in just a little bit, but I think we probably need to dive into what Alterna is doing.

7:35Most of these genetic medicines, they're still disease by disease, gene by gene approaches. Your pitch seems to be a little bit different. How would you explain what Alterna is doing to someone within the industry who understands this, but maybe someone outside of biotech too? Certainly. So it does take a bit of a mindset shift as you think about our experienced listeners, as well as people that may be more lay. So if we think about what we typically do in drug development, and especially genetic medicines, we're thinking about a gene by gene approach. So let's use an example of Gaucher disease.

8:19This is a lysosomal storage disease. If you think about developing a drug for Gaucher, right now we're specifically as an industry focused on the gene that causes Gaucher. And so a gene therapy is specifically designed to replace that gene or if it's editing to fix that gene. The same would hold true for Fabry disease or Pampa disease. I'm just using some of these as examples. So a very specific approach to a very specific disease. Alterna and our tRNA platform, we're really turning this upside down. And instead of thinking about a specific gene, we're thinking about specific mutations that are actually shared across a number of different genetic diseases.

9:12So the gene or the, excuse me, the mutations that we're thinking about are shared across these genetic diseases. And so then if you think about fixing a specific mutation, then you can think about, okay, where do we see this mutation across various diseases? And then consider studying all of those different diseases with that shared mutation. So again, you know, to simplify it, perhaps instead of gene by gene, it's mutation or variant by mutation. You've mentioned a couple of times, and it's right there in the name as well, the tRNA. We've known about tRNA for decades now. Why has it taken so long for people to actually engineer this into a therapeutic?

10:06Yeah. So, you know, I think there are probably a number of things that are a part of that. One, of course, is our understanding of RNAs generally, whether it be mRNA or tRNA, has really exploded over the last, what, decade to two decades. And so thinking about the, one, structural aspects of transfer RNAs or tRNAs, thinking about the chemical modifications, thinking about things like stability, and then ultimately manufacturing and delivery. So there are a number of complexities as exists throughout our industry and across different development programs that the company really had to think about and consider as we brought AP003 forward.

10:59Walk us through what actually happened with tRNA. What are you actually addressing and how's it working in the body? Certainly. So most people are familiar with mRNA or messenger RNA. We think of that as the genetic code. So the tRNA is a critical piece of actually taking that code and translating it into actual functional proteins. So proteins being using enzymes and different molecules that have functioned throughout our body. The tRNA actually takes the mRNA and is reading it. So in combinations of three, it sits down on the mRNA and it actually says, okay, what does this code mean for the amino acid that is supposed to be in this growing protein chain?

11:57So really, the tRNA is a very critical function of taking mRNA into the proteins that are used throughout our bodies. There's something else that comes up when I read about Alterna, and that's these nonsense mutations, nonsense mutations. Tell me a little bit about those and why you're starting here. Certainly. So as we talked about earlier, there are many, many genetic mutations that can cause diseases. And there are, you know, multiple categories. One would be nonsense mutations, which we are currently focused on. Others like missense mutations. And these basically just mean what does it do to that process we were just discussing from mRNA to protein.

12:46In the situation of nonsense mutations, the nonsense mutation actually leads to a stop signal. So that translates into something we would call a stop codon. So instead of it being the code for an amino acid like it's supposed to be, the code actually is telling the body that it should stop making the protein. And in nature, we have lots of those that exist normally because we do need proteins to stop being manufactured. But in the situation of a genetic mutation causing a disease, that stop signal comes too early in the protein manufacturing. So these nonsense mutations essentially are telling the body to stop making a protein too early.

13:41And then you don't have the functioning protein that you need, ultimately leading to disease. So in the situation of our tRNAs, specifically AP003, it reads through that, recognizes that, oh, this is not supposed to be a stop signal. This is actually supposed to be the code for a specific amino acid. goes out, finds that amino acid, brings it back, places it into the protein chain, and then that protein is growing appropriately as a functional molecule. Let's talk a little bit about AP003. That targets one specific mutation, really specifically there. Why do you choose this mutation ahead of all of these other nonsense mutations which might be there?

14:32Certainly. So first, the choice of nonsense mutations. In nature, there are only a few nonsense mutations that exist that cause these stop signals we were talking about. So in fact, they're approximately 19. And so this is a very contained universe of these stop signals, as opposed to, I mentioned earlier, missense mutations. You know, there are hundreds, maybe thousands of missense mutations, and they're different across different genes, whereas the nonsense mutations are conserved across different genes. In the case of AP003, we are focused on the specific mutation ARG to stop. And so in that situation, that is the most common of all of the nonsense mutations that exist.

15:30And they exist, again, across all of these different diseases. So as we looked at this universe of 19 different stop signals, ARG was the most common. And it allowed us to look at, you know, a higher prevalence of this specific mutation as compared to some of the other stop signals. You've now got approval to start your phase one down in Australia. What is success going to look like in that first trial? What are you looking for? Certainly. So, you know, we're obviously incredibly excited to be taking the first tRNA into human clinical trials. It is a phase one study. It's being run in healthy volunteers.

16:18And so with that, the key focus is generating safety data as well as pharmacokinetic data. So this study doesn't have an efficacy signal because it is being run in healthy volunteers. But that safety piece, as well as the pharmacokinetics, will help us set the foundation for AP003 as we think about moving into clinical trials with patients, especially thinking about things like dose finding. Your preclinical data, you must have felt pretty confident with moving forward from there. What was it like for you and for the team when you see that confidence-inspiring preclinical data and think, okay, we might really have something here?

17:06Yes. So I actually joined the company around the time some of those data were maturing, so I can specifically speak to this. You know, we have shared data in a couple of different animal models, and the data are very compelling from the standpoint of demonstrating that protein production we were talking about earlier. So we've been able to show that we can restore protein manufacturing in these animal models, as well as many, many in vitro cell models as well. But more importantly, perhaps, is not only showing that we can restore the protein, but we actually can show that that protein is functional.

17:53And the way we do that is looking at the downstream effect of the protein itself by looking at some of the biomarkers in these animal models. So very interesting set of data, very compelling, and obviously led us to taking AP003 to the clinic. now AP003 as I understand it it's not a one-time treatment this is something that you'll be dosing and re-dosing how are you thinking about the practicalities of doing that how do you manage logistics for something like this certainly so I think you know there are many many different examples of drugs that are chronic therapies in the rare disease space and in the the non-rare disease space as well.

18:41So, you know, I think generally speaking, this is a well-trodden path. The therapy is delivered by an IV infusion. And as I think about one of the sort of analogies is the lysosomal storage disorder space, where patients are able to receive their therapy even in the home setting from a home nursing situation. And so, you know, again, this is a path that many, many patients require. In addition, I think, you know, there's a safety element here of the drug can be stopped. The drug can be modified from the standpoint of doses. So there is flexibility that comes with a chronic therapy like this, as opposed to, We talked earlier about gene therapy or gene editing, which is a more permanent situation that you've delivered it.

19:40It's there. It can't be taken away. And so we see some real pros from the standpoint of a chronic therapy like this. I want to come back to something you mentioned just near the start of our conversation, which are these basket trials. You've talked in the past about tRNA being really perfectly designed for basket trials. Give me an example. What's a basket trial and how receptive has the FBA been to this sort of testing? Sure. So going back to the mechanism here and this shared genetic mutation, the way we're thinking about this is to think about a group of patients with diseases that are similar and have that shared mutation.

20:31And the importance of those similarities across the diseases is in the clinical trial design, where you're thinking about things like efficacy endpoints that are the same or similar across a number of different diseases. And so for AP003, we're thinking about inborn errors of metabolism, where many of these diseases have the same clinical efficacy endpoint or similar biomarkers across these diseases. So they can be combined in one clinical trial, treated with the same drug, AP003, and studied, as opposed to thinking about taking one single disease, studying that, the timeframe, the, you know, recruitment issues.

21:26But here, we're able to combine them. And it ties also back to what we were talking about earlier from the standpoint of not only being able to look at clinical recruitment feasibility of one specific disease, but combining them allows us to bring in patients with diseases that may not be feasible to study if you were only studying that single disease in one clinical trial. Now, this is a tried and true path in the oncology space. We have not seen it as much in rare disease, although we are seeing more and more interest, and there are now some great examples of it. So it's definitely something that has been done.

22:15We know it can be done. From the standpoint of the health authorities, you know, I think they are also showing interest, and we've had some productive conversations. All of this, as we talked about, is a puzzle to be put together. And so ongoing discussions as we continue to generate data, I think will continue to not only move us forward at Alterna, but move the rare disease space forward, generally speaking. I know I'm coming back to practicalities, but if your phase one is successful, it moves through. So phase two could span 10 or a dozen different liver diseases all at once. How do you design a trial like that operationally?

23:01Isn't it just making things even more complex than a clinical trial already is? Right. So first, before we move from the healthy to that basket that you were just mentioning, We are planning to do a study in people living with phenylketonuria or PKU. These will be adults where we're able to show, again, the AP003 and the protein generation, as well as that biomarker reduction. So the goal there is thinking about delivering AP003 in an adult population to build the evidence to move into the younger patient population or pediatrics. So then, as you were asking about the basket trial, so it's not that a basket trial necessarily makes clinical development more simple, but I think what it does is it allows us to get to those patients that drug development may just not be feasible for based on patient numbers.

24:14And so the way we think about it is thinking about inclusion and exclusion criteria that, again, are shared. So we're not talking about any patient with the ARG to TGA mutation would be in a clinical trial. Maybe one day we'll get there. But we're thinking more about that shared similarity across these diseases. And that's why the inborn errors of metabolism are really a great place for us to start with AP003, because they have those similarities where we can look at reasonable inclusion and exclusion criteria across those different diseases. So it's a challenge of getting the recruitment right rather than trying to recruit 10 concurrent trials of the same type of disease.

25:11that's right and so you know whether it's seven diseases or ten diseases or eight diseases if you thought about the time it would take to run separate trials in each of those different diseases as well as for the less common of those inborn errors of metabolism the recruitment could take years. Whereas if you're able to group those patients together, you get the efficiency of time and the efficiency of that recruitment where you're able to bring more patients into the trial, but representing a host of different inborn errors of metabolism. If we can look a little bit more broadly, what does it mean for the field, I guess, not just for Alterna, but for the field as a whole, if something like AP003 works, if it makes it through regulation and makes it to market, how does that change the landscape?

26:17Certainly. So I think it ties back to, one, the basket trial approach in rare disease. You know, for patients, this would be something that hopefully helps along with others to set a foundation that basket trials become more and more acceptable as a clinical development strategy. and the ultimate people who win from that are patients. So I think, you know, in my mind, that's really the game changer. But as we think about it at Alterna, AP003 is foundational to thinking about what is the next tRNA therapy we develop, one, But also, how do we utilize AP003 across other groups of diseases with potentially other delivery mechanisms?

27:15So there's possibility. And again, it really ties back to possibility for patients that really have not been well served in the rare community. If that's the field then, what about Alterna? Where do you see the company being in five years' time? Certainly through phase one, but what else is on the menu? Yes. So it's very exciting to think about this. So, you know, in five years, I really hope that we have shown in humans that AP003 is able to establish functional protein and have that impact on biomarkers and efficacy endpoints. So that would be one. And then tying back to all of those other opportunities, thinking about those options of other tRNA therapies, as well as how do we get to other groups of rare diseases.

28:20For the scientists, for the entrepreneurs listening who are thinking about this translation level therapeutics, what's a lesson you could offer to them from Alterna's journey so far that they could take on board? Sure. So I think this probably applies to our industry generally. But, you know, drug development is not always straightforward. It's not a linear path. But we really have to try. You know, when you have a new idea that maybe no one has paved that path before, that would be true of tRNA therapies. You have to take that risk and challenge and move forward and take a step forward. You know, figure out what is the regulatory path, just as an example, going to look like.

29:19and learn as you go. And then you're the one paving that path for the next person that comes along, the next company that comes along, thinking about something that maybe hasn't been done in a tried and true fashion before. But without that, we lose innovation, right? That's so true. Where can people go to learn a little bit more about what you're doing at Alterna? So our website has a lot of information. That's alterna.com. We're often very, you know, posting on LinkedIn as well, some educational materials. And then you can certainly find us at various conferences that we're attending. But all of that would be on our website.

30:10Fantastic. Narissa, thanks for joining us today on Beyond Biotech. Thank you for having me. 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 thanks for listening and I hope you'll join us again next time for another Beyond Biotech