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Business Of Biotech
Leading A tRNA Startup With Alltrna's Michelle Werner
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On this week's episode, Michelle Werner, CEO at Alltrna, talks transfer RNA (tRNA) therapy with host Ben Comer and guest co-host Anna Rose Welch, editorial and community director at Advancing RNA. Werner explains why a single engineered tRNA therapy has the potential to treat "hundreds, if not thousands," of rare genetic diseases, and how her own child's rare disease diagnosis shaped her career and approach to drug development. Werner also discusses Alltrna's use of AI and machine learning for drug optimization, the company's planned use of basket trials, and more.
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This episode of the Business of Biotech is brought to you by Avantor. Every day, science has the power to change lives for the better. Avantor partners with the scientific community, pioneers and innovators in the lab and in bioprocessing to help solve complex scientific and operational challenges. Avantor delivers end-to-end support, from discovery to commercialization, for the global biotech and biopharma ecosystem, providing mission-critical products and services that are integral to advancing life-changing innovations for patients. Visit avantorsciences. com for more information. Welcome back to the Business of Biotech. I'm Ben Comer.
Anna Rose Welch:And I'm Anna Rose Welch.
Ben Comer:And we're both excited to speak today with Michelle Werner, CEO of Alltrna. Michelle has worked at some of the biggest biopharmaceutical companies in the world, including Novartis, AstraZeneca and Bristol-Myers Squibb, but has now moved into company leadership at a relatively new transfer RNA or tRNA oligonucleotide therapy developer, Alltrna, backed by Flagship Pioneering. I want to thank Anna Rose, editorial and community director at Advancing RNA, for bringing Michelle to the Business of Biotech and for joining us on the podcast.
Anna Rose Welch:On today's show, we're going to get to know Michelle and find out why she wanted to take a chance with a tRNA startup, as well as what makes tRNA therapies unique and promising. We'll also learn about the many challenges that come along with working in a new therapeutic space in terms of attracting investors, designing trials, manufacturing therapies and working with patients and regulators.
Ben Comer:Michelle, welcome to the show.
Michelle Werner:Thank you so much for having me. I'm really excited to be here.
Anna Rose Welch:We're excited to have you.
Ben Comer:Yes, we are. As we alluded to in the intro, you've spent a majority of your career at Big Pharma, working in commercial functions and as a country head and franchise head, both in the US and globally. How did you get connected in with Flagship Pioneering initially?
Michelle Werner:So I mean, in some cases it was a little bit of luck, I guess I would say that I got to a stage in my career where I was looking to do something a little bit different than I had done with the previous 20 years in my career. So, as you've mentioned, ben, I've been in big pharma for much of my career 20-ish years. Most of that has been focused in the oncology space and I will say that I had a really phenomenal career in big pharma. I had a you know have really great experiences and memories of my time at those companies that you've referenced and I found this space to be extremely rewarding, especially in oncology, of course, where there's huge unmet medical need. I got into this drug development business in the first place because of me having worked in a cancer clinic, so I really was working hand in hand with patients and really understanding what their needs are and what they go through, and for 20 years that was a really phenomenal place to be and during that time I got to see the emergence of some novel therapies come through. When I first started it was chemotherapy and maybe chemo doublets were emerging, but you know, during my time I saw the emergence of targeted therapies, I saw the emergence of immunotherapies, immunotherapy combinations, and that really changed the overall trajectory for patients with a lot of these different cancers and was a really phenomenal place to spend much of my career.
Michelle Werner:But, as happens sometimes in life, right, different curveballs get thrown your way, and one such curveball was a very personal circumstance and it was actually in May of 2020. So, just about five years ago now, one of my three children was diagnosed with a rare genetic disease and, in fact, he was diagnosed with Duchenne muscular dystrophy specifically, and it happened to be on his 10th birthday. And as a drug developer, right, the first thing that I think of is okay, well, I know a little bit about medicine and how to treat disease and, you know, let me wrap my head around everything that there is to know about treating Duchenne and I realized that the standard of care was, you know, not really great, with basically high dose steroids essentially as the mainstay of treatment, which you know may be beneficial but also comes with a lot of side effects. And then so I was treatment, which you know may be beneficial but also comes with a lot of side effects. And then so I was like, well, that standard of care isn't good enough. So what else is out there? And I did what a lot of drug developers would do, and that would be go to clinicaltrialsgov and see what innovations were in the works. And even perusing the few pages of Duchenne trials on clintrialsgov, I realized there was not a single one that my son was eligible for not a single one. And that was heartbreaking, really, really heartbreaking.
Michelle Werner:And so, basically, you know my, it really cast this spotlight on the inadequacies right of treating rare diseases or the innovations that are available for rare diseases versus more common diseases like cancers. And I was, you know, I realized that it was an appalling situation and I felt like, after some deep reflection of not just our personal circumstances having changed but my own professional circumstances, it made me realize that, okay, in 20 years in oncology we've made a lot of difference maybe not a self problem, but a lot of difference. I want to spend the next 20 years and focus on genetic diseases, rare genetic diseases in particular, because I really personally felt the sheer unmet medical need and what it was like to actually feel like you were a patient that was completely overlooked by the industry that I love being in and that I had been in for the last couple of decades. So that was really the sort of backdrop to what was happening at the time, and so to me I was thinking, okay, maybe big pharma isn't where I want to be, maybe I need to be in a nimble, dynamic biotech environment.
Michelle Werner:But then, honestly, it was really when I was first told about Alltrna specifically that it made me really realize the sheer potential of our platform with our engineered tRNAs, because the whole idea behind what we're doing is one single engineered tRNA may be used to address hundreds, if not thousands, of different diseases, and as a rare disease parent, I know that there are somewhere around 10,000 of these.
Michelle Werner:You know rare genetic diseases and with today's technology, even the novel ones like gene therapy, gene editing, mrna all are taking a one disease at a time strategy, because that's how those modalities work. But if you can turn that paradigm on its head and find a way to use a single medicine to address hundreds of them, you could clearly appreciate the transformative potential that that kind of technology might be able to have on this patient population, whereby most of those diseases do not have an approved therapy In fact, 95% of them do not. So that's really why I came to Alltrna. It was also great that it was a flagship, pioneering company. To be honest with you, that was an added bonus Because, as a first time CEO, being part of an ecosystem of companies and an ecosystem of expertise was very attractive to me.
Ben Comer:Yeah, and so it makes sense why you wanted to take this big swing into genetic medicines, and I think that you know the concept of a single mechanism being able to potentially solve a whole lot of diseases is very exciting. But, like you said, you're a first time CEO and I'm curious now you know you're three years into the job, is it different, you know, than you expected it to be, kind of on a day to day level, and how did you prepare for it?
Michelle Werner:So, to be honest with you, Ben, I'm not sure I had this like very preconceived idea about what being a biotech CEO would be. Like my only frame of reference really were the CEOs of the various big pharma companies that I worked for, I worked at in my career and I knew it was going to be different than that, but I didn't really know what to expect. I will say that there was definitely a period of time where, you know, I was really excited about the role and the opportunity, but I also didn't know, like, am I really equipped to do this job? Am I ready to be a CEO? And part of that was, you know, do I have the skills that are and the capabilities that are needed to lead a startup organization number one, a team of employees who are essentially all basic science, like scientists, basic scientists like I've. I've mostly led, you know, big teams, but big teams of commercial people in my career. So this was a fundamentally different thing. I'm more of a commercial person. Do I? Am I really going to be relatable to the scientists and to really understand what they're doing and for them to understand me and where? You know, my vision is? And so there was definitely a question mark about that.
Michelle Werner:And then there was also, you know, as with any CEO in a startup environment, especially a private company, it's a lot of focus on fundraising, of course, and it's not something I've ever done before, right. So I've had some investor interactions in my previous executive roles in pharma, but not a lot and not where I'd have, like, the sole responsibility really of, you know, making sure that we can, you know, have a capital formation strategy that's successful. So I'd say there were some uncertainties coming into this role, but there are a few things that I learned and kind of getting to how I prepared, which I think you know, honestly, looking back now, the 20 years that I've been in the industry actually was the preparation that I needed for this job. So, even though I've never had the responsibility of raising capital for a company in the past, what I did do a lot of in those different companies is put business cases together to create a compelling story about a strategy that we want to invest in as a company and to secure the resources within those companies in order to be able to put behind those ideas. It's essentially the same competency, I'd say, when you're gearing up for, let's say, a Series B, as we had to soon after I joined Alltrna. So I'd say a lot of that sort of skill was transferable, which I didn't know at the time, but certainly was the case.
Michelle Werner:And then I would just say, more broadly, around the leadership skill, I mean, of course Alltrna is a much smaller company than most of the teams that I've led before in the past and again a very different phenotype of employees than I've led before in the past.
Michelle Werner:But there are a lot of things from a leadership perspective that are transferable from one gig to the next, from one employee base to another. And actually really just trying to paint a picture for what it is that we're doing and what we're trying to achieve with the really cool science that we're developing at Alltrna is something that I feel like I've had to do in any number of my leadership roles in the past. Paint that picture for a vision. You know how to make strategic choices that are going to help enable that vision to be materialized. And I'd say, in particular with this team and with this company, the fact that I'm actually a rare disease parent as well resonates with the company and you know there's not a day that goes by that I think the Alltrnators, as we call ourselves, don't love the nicknames.
Anna Rose Welch:Yeah, it's great.
Michelle Werner:That we don't, that we I mean every single day. I think we appreciate that we're doing cool science, but we're doing science with a purpose and that purpose is to really transform the care for patients across a number of different rare diseases, and I think my personal connection to this community is uniquely suited to to help bring that to life.
Anna Rose Welch:You are I mean you. You expressed really nicely why tRNA right, like why that molecule itself spoke to you and sort of through your journey into leadership of a small biotech company working with a tRNA product. I'm really curious. You know, outside of the mechanism of action of it, what was the most exciting reason for you right to sort of jump into this really novel scientific space and how had you, or how have you right continued to learn more about that scientific element of this brand new science, right? How can you share a little bit more as well about, about how you've prepared your leadership to sort of fit into this more scientific niche Right and in a new biotech?
Michelle Werner:Yeah, so I mean, maybe just you know the like, the coolest thing I think about the tRNA, like, as I said, is the ability to transcend different diseases, and when I was first considering this role and I met with some of the founding scientific team, you know some of the initial like preclinical data sets that they showed me, which showed that a single engineered tRNA was able to restore protein across, you know, almost 25 different disease models in cell models and, and that it was able to do that regardless of which gene was affected, which protein was being coded for, and actually the location of the mutation also did not matter. It was able to restore protein or read through these mutations in each one of those settings in a very universal way, which is not something I've ever seen achieved with really any other modality that at least I was familiar with, and so I found that to be like, truly, you know, like I said, could be very transformative, Because that really said to me like, even if I just take Duchenne, for example, which is a disease I know very well because that's the one that my son happens to have In Duchenne, now there's a gene therapy that can be used across, you know, all patient types, or most patient types, not all but most. But before that there were actually exon skipping technologies, which meant that you had to have a mutation in a certain place that would be amenable for those types of technologies. And guess what? My kid did not have that mutation. So there were many approaches that just were not possible for my own son and gene therapy is the same way, by the way, it's not depending on the mutation location or depending on baseline antibodies or a lot of other different reasons right, May not be an appropriate therapy.
Michelle Werner:So having a drug that might, or having a modality that might be able to transcend some of those nuances, I thought would be like truly, truly interesting. And so that to me was like I'm hooked. I was really hooked on that general idea from the outset. And then, how did I really prepare? I mean, I will tell you, you know other than my biology 101, you know class right back from college books. Yeah, I mean I don't think I ever said tRNA in my lifetime, I mean.
Michelle Werner:So there was a lot that I really had to learn.
Michelle Werner:So the thing to me was the big picture idea I got, and then to me it was really about like digging into the science and understanding the science.
Michelle Werner:And and that's where I would say is, you know, I got really invested in it, and so I felt like the basic thing that I really needed to do was really just listen actively, listen to all the incredible scientists that we have here at Alltrna to really understand. This is the opportunity, these are the challenges, this is how we think we need to translate this modality, or translate the science, into a new therapeutic modality for patients. And it was really a lot of listening and learning and that, to me, I'd say, was, I mean, that's where I spent most of my time in the first few months, listening and learning, asking a ton of questions and really getting up to speed. And then, once I sort of got the basic fundamentals of the tRNA biology that sort of kind of, I'd say, positioned with the drug development experience that I acquired in my, you know, couple of decades of being in the business, I was able to start making some connections between the biology and you know, ultimately, at the end of the day, what we're trying to do for patients.
Anna Rose Welch:There are a lot of connections right between all the different modalities that you can definitely make.
Ben Comer:I want to. Oh sorry, anna Rose, I cut you off there.
Ben Comer:No, I just I wanted to pick up. I'm curious about the investment piece and you've talked about some of those skills being transferable from previous work you've done in big pharma. But I have to imagine that when it's a brand new modality, never been a drug approved there has to be. Well, correct me if I'm wrong. There must be some bit of education that you have to do with investors and I'm just sort of curious about this. The story obviously is so important for an investor and I just wonder, you know if you might share kind of how that experience has gone. Have you had to explain not only how the mechanism works but kind of make it real for investors and say this is why we think this is possible?
Michelle Werner:A hundred percent Right. So that's exactly how we've really teed things up for investors. I mean, honestly, I always really start a lot of these conversations with you know, let's just talk about the unmet need, right. The numbers of diseases there are 95% don't have an approved therapy. We're trying to tackle it one by one, kind of just like the conversation we've just had a little bit, to really sort of like appreciate the sort of what seems like an insurmountable challenge that we have in the world of genetic diseases. That's basically where I start.
Michelle Werner:And then, yes, just like I needed a foundational understanding of what is a tRNA, what's its function and why do we think it has this kind of universal ability. We then talk about the specific types of mutations that we're tackling in the first instance. So we think a tRNA can address a number of different types of mutations, but we have to start somewhere and we are starting with nonsense mutations. So with a tRNA we're taking this approach of identifying those common nonsense mutations across a number of different diseases and why you know why we see the same nonsense mutations from one disease to the next and why the sort of conserved biology of a tRNA should be able to address all of those. And then it is about, like, giving a reason to believe. Right, we all need reasons to believe, just like I needed a reason to believe to join Alltrna. Investors need a reason to believe that you know that this isn't just a crazy idea, that this crazy idea actually might have legs to it, and that comes with data. And so, with our Series B, which we announced raising 109 million in August of 2023, which you know, we're really very proud and excited about, that was really based off of mostly I mean a preclinical data set that was mostly based on in vitro data, with one small piece of in vivo data, our very first piece of in vivo data. And now, you know, we've been able to progress the platform as such to now have multiple in vivo data sets across multiple different disease models, and now we're demonstrating that what we saw in in vitro environments across multiple diseases now is similar in the in vivo or mouse setting, which is also super exciting. So, if you see translation from cell to mouse, the likelihood of seeing a translation from animal to human is much, much higher. So that's what we're really excited about. So yeah, you have to tell that story, but then I would say also, in addition to telling that story from the basic kind of biology, is also how we're planning to develop our tRNAs, because this is also a little bit, you know, I'm going to call it somewhat unconventional, although it's been used before in the past.
Michelle Werner:So certainly some investors who've been around the block, especially in the oncology space, would be familiar with this, because this is what we call basket trials. You may be familiar with them but it's been used very commonly in oncology. In fact, I'm going to say seven or eight different drugs got approved using a basket trial strategy. And what a basket design is is basically patients have technically different diseases. So in oncology it could be lung cancer or breast cancer or, you know, ovarian or anything you kind of put. You know, fill in the blank, but each patient is selected by having a common mutation. So, again in oncology, it could be the EGFR mutation, for example. In rare diseases it could be a specific nonsense mutation. So patients technically have a different disease, but they're all selected by having that same common mutation. Across those different diseases. They're given the same drug in the clinical trial and then they're monitored right, maybe for the same things, maybe for different things, and that's what we're doing in rare diseases.
Michelle Werner:So a common development strategy in oncology is now going to be applied in rare diseases.
Michelle Werner:It has before in the past, but to a lesser extent in oncology, but now we have a modality like a tRNA that actually is uniquely suited to take advantage of the basket trial design.
Michelle Werner:And what's great about that is is that not only in this clinical trial can you include the more common of these rare diseases, you get to also include the ultra rare diseases as well, and that, honestly, is really the most exciting thing, because those ultra rare diseases will likely have, maybe never a clinical trial or an interventional clinical trial in a patient's lifetime. That's the reality, which is really really, you know, heartbreaking when you think about it. So I really love this strategy because of this idea about bringing all these patients together and unlocking not only what we hope will be an innovation that will be beneficial to these patient populations where there are essentially no effective treatments, but actually, from an investor perspective, it really unlocks a value pool that is currently completely locked right now, because there are no drugs that you know or no company that is specifically going to focus on these ultra rare conditions really mostly because those individual patient populations in and of themselves are too small If you have to take one disease at a time strategy.
Ben Comer:So now we all of a sudden you know, and that's how we sort of paint the picture of the opportunity to investors. So with you will be kind of out of the gate, pursue a basket trial, multiple disease arms from the very beginning. Or will you do some initial early stage like safety stuff before you start? You know, go into a basket trial.
Michelle Werner:Well, that will definitely be a decision that we make in in combination with input from health authorities, and you know we are working through that right now. So some of those details are still remaining to be seen, but the idea for us is to get into a basket trial as quickly as possible, right? So maybe we do need to do a small first step just to be able to demonstrate a quick clinical proof of concept or a quick safety data set in humans. You know that matches the preclinical data package that we've already developed, but the idea is for us to be able to get to a basket trial as soon as humanly possible. And so, because that's where we think we have the most potential to be able to add value to the patient- populations and really to demonstrate what a tRNA can do across a number of different diseases.
Anna Rose Welch:Well, I think, as the parent of a patient with a rare disease, right to the scientists, the people working within your company, and even just some of the work you're doing now, thinking about the strategy for delivering and developing a rare disease product, right, I'm curious if you can share a little bit more about some of the? You know new skills you've had to develop, right, you've been able to carry a lot of the work you've done as a leader. You know new skills you've had to develop, right, you've been able to carry a lot of the work you've done as a leader. You know into the work you're doing at Alltrna, but in what ways has working with tRNA you know, kind of differed, you know, and what new skills have you had to develop in order to best?
Michelle Werner:Yeah, I mean, first of all, I will say that it's been a really, really, really long time. I mean I did some basic science research at the very, my very first job outside, like once I graduated with my university degree. But I mean to go back to basics really like to really understand the cell models and cell cultures and you know what is a Western blot and you know like all kinds of things that honestly, I just really not had to think about in the last 20 years. So a lot of it was really kind of getting back to what actually happens in the lab and what are we really trying to achieve and and and really I'm going to say brushing some of that off but then developing a completely new vocabulary there that I probably didn't have even, you know, given my time there. So that was definitely something new for me. But then also, you know what I would say is I spend a lot of time in my current job interacting with patient advocacy groups.
Michelle Werner:Now, I did a little bit of that in my previous life or my previous professional life, but not so much actually. I've done a lot of it as a patient caregiver, right, so I've had that experience, but I really haven't had the experience of really developing those relationships and those connections and really you know using those interactions with across a number of different patient advocacy groups because, as you can imagine, with the technology that can go across many different diseases, I speak to many different patient advocacy groups or who are almost exclusively organized by disease and you know to really like learn how to like be a deep, deep, deep listener to understand their point of view on, you know, different endpoints that are really important and relevant to them, different ways of designing a study, even just like picking their brains about, you know, like are patients getting tested for different mutations? Where are they actually getting seen? Like, really like asking a ton of questions of them. I haven't had to have that level of engagement with patient advocacy groups, probably ever in my lifetime, and so that was definitely something that was new for me, but I will say, fortunately, something that came pretty naturally.
Michelle Werner:I'd say probably, because I was on the other side of the table and have been for the past few years since my son's diagnosis, not only as a member of one of these rare disease communities, but actually my family started our own nonprofit after he was diagnosed.
Michelle Werner:So I've had some of that you know experience as well. So but those are things like for me, like really we've taken very seriously, really tried to do as much of that as humanly possible, even for an early stage company like us, where we're not even in the clinic yet, but really being able to bring different stakeholders along on this journey with us. Because one thing that I've really learned a lot in the rare disease setting is there's no one person or no one company or no one team that has all the answers to addressing these complex medical situations. A lot of it has to come through really a partnership perspective leveraging the knowledge base that exists, working together to try to fill the gaps on where those you know the knowledge gaps currently are, and then coming with a unified approach on how we're going to tackle data generation or interactions with regulators and things like that, which has all been, you know, I'd say, mostly pretty new for me.
Anna Rose Welch:Yeah, I would say so. Do you have like any helpful practical best practices for other early stage companies like yours, right that? Are you know, from the top down right embracing that patient-first mindset? Do you you know what would you encourage other CEOs in your position right working in this rare disease space? How can they continue to get to know their patient advocacy communities?
Michelle Werner:Yeah, I mean. So to me, I would say, first and foremost, it's start early, right. I'd say. Oftentimes people don't engage until you are right at that stage of having a clinical trial and, quite honestly, I felt like that was going to be way too late. So, you know, I started when I first joined, you know, three years ago. So I probably had my first engagement with a patient group, you know, within the first few months of me being in this role. So I'd say, start early, early, early right, it's never too early to to engage with a patient advocacy group.
Michelle Werner:However, right at the same time and I say this also now as a, as a parent it's also really important to not try to oversell something and to be very pragmatic about what the expectations are, because the last thing you want to do is to make a promise that you can't keep.
Michelle Werner:So I think there's a real balance of like, how do you make a connection, get the insights that you need that are going to be really important to shape a program moving forward, and that you can start developing a relationship, but also in a way where you, you know, aren't saying that you're going to cure these diseases, that they're very focused on. When you don't we don't necessarily have those data yet to be able to say that. And so, to be very, very kind of practical about what those expectations are, kind of practical about what those expectations are, We've seen many times, you know, companies come into a disease area and then, unfortunately, something happens, whether it's, you know, data driven or funding driven, and you know those programs can't continue, and it's really heartbreaking, right as a patient or as a family. And so I think, really being sensitive and in tune to that is something that I think is so important, so important. So, start early, establish those relationships, build it over time, but bring people on a journey with you. That's also, you know, based on in reality.
Anna Rose Welch:That's great advice greater place.
Ben Comer:Michelle, can you explain the concept and implications of reclassifying patients with genetic diseases into a stop codon disease" category?
Michelle Werner:Yeah, so right, we call it stop codon disease.
Michelle Werner:So again, you heard me reference the 10,000 different you know different genetic diseases out there, and that's the equivalent of hundreds of millions of patients around the world would have one of these types of genetic diagnoses. Now about 10% of all those genetic diagnoses are diseases that stem from a premature termination codon or a nonsense mutation. As we've been talking about a nonsense mutation, and just for reference, if people are unfamiliar with what a nonsense mutation is, this is where a code for an amino acid in the protein translation process unfortunately codes for a stop instead, and that means that instead of translation continuing from beginning to end, the translation stops where it has this mutation, and that's too early. So the result then is a truncated or a dysfunctional or sometimes even an absent protein, and that's what causes disease. So about 10% of all of these genetic diagnoses come from a premature termination codon and collectively we would call that as a premature termination codon and collectively we would call that as a patient having stopped codon disease. Now roughly about 30 or 35 million people around the world would have, you know, fall into the category of having stopped codon disease. Now I'd say the idea about reclassifying those patients is really important because what's happening today, with all the other technologies and all the different modalities that exist, like I mentioned, whether it's gene therapy, gene editing, mrna, most small molecules, asos, for example all of them are very specific to a disease or a protein.
Michelle Werner:And so when you are one of these stop codon disease patients and let's say the stop codon disease is in phenylketonuria, or the stop codon disease is in methylmalonic acidemia, these just happen to be rare genetic liver diseases where we're focusing first, but it could also be stop codon disease in Duchenne muscular dystrophy. It could also be stop codon disease in Rett syndrome, for example. Right, these, you know, these stop codons exist across almost every single disease and right now, what patients need to do is wait for individual treatments for each and every one of those diseases. Now, again, coming back to 10,000 different diseases, unfortunately, most of those diseases will never have an FDA approved drug as they do today. Most of them I mean only 5% do so instead of when you treat patients by stop codon disease.
Michelle Werner:That means that, instead of a patient needing to wait for an individual treatment for each and every disease within that category, perhaps a single engineered tRNA may be able to address patients across thousands of different life-threatening conditions. That's the real potential of what we're aiming to do at Alltrna. Now that sounds easy. It's not easy, of course, but that's really the idea behind. You know the reclassification of so many different patients across so many different diseases into, let's say, a few universal diseases that can be treated by addressing those common mutations that exist across all of them sound very easy at all to me.
Ben Comer:I you know, I know that that Alltrna is is leveraging AI and machine learning and I wonder if you could just discover how those tools factor into your discovery and drug development. I mean, is that how you landed on nonsense mutations for your kind of initial look?
Michelle Werner:It wasn't how we landed on non-sense mutations, but it definitely has helped us land on our development candidate AP003, which is moving forward, and all of the other kind of best tRNA designs that we're advancing. So let me just share with you about how we're leveraging that. So, just taking a step back, how we design tRNAs is by using two-pronged approach. First we optimize for the sequence of the roughly 75 nucleotide structure oligonucleotide right that makes up the tRNA. That's one way. And then the second thing that we do is actually then optimize those tRNA structures with different chemical modifications, essentially decorating those structures with different modifications that we think are really important to enhance different properties of the tRNA, such as how well they read through these nonsense mutations and what their potency is, for example, maybe even their metabolic stability. Those are things that can be engineered for. So the tRNA sort of combinatorial space is actually massive. So there are more tRNA patterns than there are atoms in the universe, right? That's a lot right.
Michelle Werner:I don't know exactly what that number is, but it's a lot, and so, of course, even the brilliant scientists that we have at Alltrna cannot wrap their heads around. You know one tRNA design versus another, not to mention trying to really understand and hold the knowledge of. You know more atoms in the universe, tRNA designs right they can't.
Michelle Werner:Come on, they can't.
Michelle Werner:I mean, we're really good but not that good, really good but not that good. So you need a machine learning engine that really underpins the platform that we have at Alltrna, that is really understanding the design rules of our tRNAs in ways that are well beyond any brilliant human brain can achieve, and so what it is helping us to do is really to understand in a very predictive and generative way, that certain tRNA designs are going to have a certain outcome. Like you know, they're going to be more active, they're going to be more potent. They, you know, may be able to protect the tRNA that can create it to be a more stable structure. And then we take all of these sort of like learnings from the machine and our scientists then apply those learnings in a rational way into our tRNA design process. So I'd say it's a very it's a very sort of comprehensive way of designing these tRNAs, that it's not just built on machines, it's not just built on human brains, it's really the combination of the two. That's our secret sauce, that makes the magic happen.
Anna Rose Welch:That's what I've heard. Right, it's you can't just rely on the technology, you can't just rely on the human, it's you got to have both. And I'm curious you know there's AI and machine learning are obviously huge buzzwords right in the in the industry today, and so there's, I'm sure, a lot of different technology platforms out there right that you can pick from and work with. You know how are you and your team kind of deciding what's the best right fit for your uses, for your for tRNA right To help you conquer the giant universe of tRNAs?
Michelle Werner:Yeah, I mean, I'd say for us, right, like all of the like, the machine learning engine that we're using is generally data that we're generating ourselves.
Michelle Werner:Right, it's not like we're accessing or buying or right. But the good news is is that, in addition to what we're doing at Alltrna, of course, there's a gazillion things happening in the environment around us, and one of the beautiful things about being in the flagship pioneering ecosystem is that there are capabilities within flagship pioneering that we don't necessarily need to be experts in at Alltrna, but we can tap into. So, for example, when it comes to AI and and ML, there's a group within flagship that's called pioneering intelligence, and this is like what they do, right? This is their bread and butter, so, and they know about Alltrna, of course. So the great thing about that is, like, with all of the work and the explorations that they're doing, if they see that there's, you know, a tool or an asset or a fit for our platform, you know it would come to our attention. Some like one way or another, without us necessarily trying to stay on top of all of that advancement that's happening in the field. So that's one of the beautiful things about the ecosystem, for sure.
Anna Rose Welch:I was going to say, do you have to do a lot of other types of investments as well? Obviously there's. There's this help right through this ecosystem, but have you had to hire different types of personnel or purchase different types of technologies, establish new internal departments, Like, what kind of investments have been really required to to help build these, these capabilities and this know-how internally?
Michelle Werner:Yeah, I mean I would say you know computational biology and computational chemistry are definitely capabilities that we've brought in-house and are developing in-house. So that absolutely is very consistent with you know us to be able to continue to leverage the machine learning well, to make the machine learning even better than it is today, but then also to make sure that we're leveraging it in the best ways possible. And it's actually brilliant to see how these groups come together with. You know our biology teams and our chemistry teams and you know the computational teams together in the tRNA design process. It's super cool actually. So all those different competencies have a seat at the table.
Ben Comer:Let's talk for a minute about Alltrna's progress so far. Your lead candidate uses a lipid nanoparticle for delivery to the liver and you're currently, I think, doing IND-enabling studies. What can you say about the reasons behind choosing lipid nanoparticles as the initial delivery mechanism? As the initial delivery mechanism?
Michelle Werner:Yeah. So I would say, Ben, honestly, this was a pure strategic choice, right? You know, whenever you have a new technology, you have to make a lot of decisions, especially in early stage. And because we are very focused on, you know, as I mentioned, you know, a couple of years ago it was translation from cell to animal. Now it's about translation from animal to humans, and so we're planning for an entry into clinic.
Michelle Werner:So for us, it was a real strategic choice to use an LNP, a lipid nanoparticle, and that was because LNPs now, as you know, have been in millions of people around the world because of them having been used in the COVID mRNA vaccines.
Michelle Werner:So, and not to mention other therapeutics as well, it's used in. So it's a delivery technology that, I will say, is very well characterized, very well understood, certainly commercially available. So it's accessible for an emerging company like Alltrna. And so for us, we really wanted to try to mitigate or minimize delivery risk as much as possible, and every oligonucleotide needs to think about delivery, not just the payload. So we wanted to say, okay, how do we take care of delivery risk and mitigate as much as possible so we can focus on the tRNA, knowing that a tRNA has never been in humans before and this is, you know, going to be one of the you know, maybe the first time it's ever been in humans.
Michelle Werner:And so to really focus on what the tRNA payload can do, its safety profile, its efficacy profile, knowing that a lipid nanoparticle is very effective at getting to the hepatocytes, which is the cells that we need to target for our initial basket of diseases that we're aiming to enter into, it was a strategic choice, so it was about not having two novel technologies at the same time, but really focusing on one novel technology with one de-risked technology, and that seemed to be like the best strategy so that we can get that clinical proof of concept, which is going to be critical for us to unlock the potential of our platform much more broadly, have you started to think about a manufacturing scale up?
Ben Comer:I mean, I assume that you're probably manufacturing enough for these early stage definitely preclinical, but early stage clinical trials. Well, I guess my question is will you manufacture that internally? Are there partners available for a brand new modality like this that you know that can help you scale up eventually? What's your? What's your approach?
Michelle Werner:So the answer is yes and yes right.
Michelle Werner:I mean we are planning to partner, right, and so actually we do have a couple of CDMOs that have been onboarded. We spend a lot of time as a company talking about the scaling up of drug substance and drug product and you know all of that is underway in order to make sure that we have the materials that we need for GLP-TOX and our initial phase one clinical trials. So, yes, that is moving forward as planned. We do have the possibility of manufacturing these ourselves, right. So even in the small labs that we have at Alltrna, we can do small batch sizes of our tRNAs and actually formulate them in-house, our of our tRNAs, and actually formulate them in-house. And that work is actually really critical to make sure that we understand, you know, the methods that are really required from a manufacturing perspective. So, as we are partnering with our CDMOs, that we can work with them on you know those methods, those you know that technology that scale up all of those things purification, et cetera, et cetera, that scale up all of those things purification, et cetera, et cetera. That is a critical component of the scaling for clinical readiness. We have to be experts on it so that we can be best partners with our partners to help them as we move forward. So, yeah, so we do some of the manufacturing ourselves, but really the CDMOs are going to do most of it for us.
Michelle Werner:And what I would say is the good news is is that, yes, these partners do exist. So, even though a tRNA technology is very, very new, the good news is is that siRNAs have been around for a decade. Mrnas now have been around for you know, about a decade. Been around for a decade. Mrnas now have been around for you know, about a decade, and a lot of those manufacturing competencies for those types of RNAs have been really instrumental for the sort of readiness of tRNA manufacturing. So I always say that we stand on the shoulders of giants, right, companies like Alnylam, companies like Moderna, who have come before us and have really paved the way. Yes, of course we have to do things that are specific for tRNAs, but we're not starting from ground zero, right? We're really able to have an accelerated pace from a manufacturing perspective because of all the hard work that's been done from other companies ahead of us.
Ben Comer:Have those companies similarly paved the way, would you say, with regulators? And I'm curious, you know, if you how much you could share about any kind of preliminary discussions that you've had with FDA, for example?
Anna Rose Welch:So I would say yes and no to this question. Cmc is a tricky one.
Michelle Werner:Yeah, it definitely is a tricky one, right. Yeah, cnc is a tricky one. Yeah, it definitely is a tricky one, right. So now, when it comes to the basket trial strategy, right, those other technologies, as we already talked about, cannot leverage that Right, so they're not doing the heavy lifting on. You know what the preclinical data package needs to be to support a basket trial strategy, especially getting into, hopefully, pediatric patient populations, which is where the bulk of these patients are. So that's work that, I'd say, bespokely, we're figuring out Now, granted, we're also taking cues from the oncology space, so trying to leverage as much as possible there.
Michelle Werner:But then also in certain rare diseases there have been basket trials before.
Michelle Werner:Let's say, for example, the urea cycle disorders, where, you know, other types of technologies have been able to be used across a number of those different diseases, and so there is precedence, I'd say already in the rare disease space have helped before is really, you know, thinking through clinical trial design in rare diseases, for example, and not just them but other companies as well, even big companies like Sanofi or Alexion or you know other companies like that, who have had, you know, historical roots in the rare genetic disease space. They've sort of already worked with regulators to understand okay, maybe you don't have validated biomarkers from the outset, but maybe you validate those biomarkers as part of a clinical trial. How do you, you know, think about different clinical endpoints for some of these diseases or in any of these diseases and sort of you know, thinking through what you're going to measure as part of those designs? So I would say, absolutely there is some progress that we can latch on to, but other things that we definitely need to tackle that are specific to the work that we're doing in Alltrna.
Ben Comer:Do you get a sense that? I mean, do you have a kind of I don't know, I'll let you describe it. What kind of relationship do you have with FDA? Have you had those conversations? Are they open and excited, as you are, about this new modality coming forward?
Michelle Werner:Yeah, so I would say those engagements are beginning. But what's actually super cool is, even, if you just like, listen closely to the way that health authorities and not just the FDA, but the MHRA, ema, for example the narrative that's coming from the health authorities themselves is actually very, you know, lays the foundation for this basket trial strategy and this really many diseases at a time strategy. That's how they describe it. Right, they understand the sheer problem of so many rare and ultra rare diseases. They know it. They know that they see clinical trials for a handful of those diseases and they never see a clinical trial for most of them. So they're even talking about what is the approach that can be taken. That's a many diseases at a time strategy that could be beneficial for patients in a much different way than we've been able to do before. So so that's like what's happening in the back background with the regulators, which you know.
Michelle Werner:So then, hearing about a tRNA that may be able to address so many different diseases and might be able to do so in a much faster and more efficient way, yeah, of course there are questions, because there's. It's a brand new modality. No one knows how a tRNA is going to behave in humans, and so, yes, there's a lot of curiosity and, you know, discussion that is related to that, but the whole concept of like taking a single drug and using across many different diseases is exactly what they've been almost asking the industry to figure out a way to make happen. And so now it is that we're coming with a potential solution to that problem, and you know so, yeah, so I'd say that I'm feeling good about like us being able to achieve it, but, of course, everything will have to be done in partnership with regulators, but I do think that the there's reason to be optimistic here.
Anna Rose Welch:I'm getting this like image of tRNA as a really like kick-ass superhero like in a comic book series for some reason, I don't know, I love that. Anna Rose, I love it.
Ben Comer:Thousands of enemies at once.
Anna Rose Welch:Do you need any materials for patient advocacy?
Michelle Werner:Absolutely. I'm going to call you on that one.
Anna Rose Welch:We're going to work on it, please do. I'm excited I've got some ideas, all right.
Ben Comer:Michelle, I noticed on your LinkedIn profile that you are a member of Chief, an organization that supports senior women executives. Can you tell us a little bit about that organization and and what you've gotten out of that membership?
Michelle Werner:Yeah.
Michelle Werner:So I had the opportunity to join Chief I'm going to say around four years ago now or so, maybe five. I have found it to be a great resource of other executive women leaders who are oftentimes, I'd say, you know tackling, you know certain professional challenges or thinking about a you know tackling, you know certain professional challenges or thinking about a. You know making a change in their career. And one of the best things, that when you first join chief, you're assigned to a group of around I'm going to say, six or seven other female executives who somehow are all connected to each other, although you don't know how, when you're first assigned to that group and you basically just become a resource for each other, almost like a support group for each other. So you get really real in these conversations. The first experience I had was facilitated by a moderator who helped engage a conversation across all of us, and then you start really building these relationships yourselves and become a support system for each other, even independent of the moderator, actually sometimes even independent of Chief, and but I have found it to be super great.
Michelle Werner:I loved, you know, when I first joined Chief. It was when I was making this transition from big pharma to biotech. So I and my son's diagnosis was actually super fresh also. So a lot of what I got out of Chief was how to navigate this transition and to sort of couple that with this kind of personal crisis that my family was going through, and I found it to be an incredible resource and what I actually learned is, even though my story seems very unique and perhaps probably doesn't happen to most people in their lives, actually all these women go through stuff that is different, but equally as sort of impactful or equally as challenging, right, just in a different way, and the struggles that I have might be helpful for somebody else to kind of understand how to navigate the struggles that they have and vice versa, and I have loved being part of a group of women like that.
Ben Comer:For our female biotech leaders and aspiring leaders out there. I'm curious is Chief an invitation only organization? Can anyone join after you reach a certain level? Do you have a sense of that?
Michelle Werner:I know that I had to be nominated. I'm not sure if that's changed in the last few years. So, yeah, somebody had to nominate me and then I had to be vetted and accepted. I think they are trying to make sure that you know the, the, the seniority, the level of seniority is at a stage where it can be relatable amongst the members, and so I think that's something that they're definitely looking for. But I think if you want to be a member, there are ways to become a member.
Anna Rose Welch:You're going to become a member, Ben.
Ben Comer:I don't think I'd be eligible but Anna Rose. I would nominate you.
Anna Rose Welch:Hey, hey, you should join. It's great, you'd love it. Hey, I've followed Chief for a while. I've been kind of entranced by their business model. It's really awesome. I'm curious, you know, as we're kind of approaching here, you know we're in a new year, I'm just curious how you're envisioning this upcoming year progressing for Alltrna, right, what are some of the biggest challenges you think you're going to be tackling for the company moving forward, as well as maybe some of the challenges as a leader you're going to be taking to chief for some help, right? Yeah, your network.
Michelle Werner:Well, it's, it's true, right. So what I would say is I mean, first and foremost, we're at a pivotal stage as a company, right, we have our development candidates in the IND enabling phase. So of course that means that we're going to be, you know, making that transition from a pure research stage company to a research and development almost equally weighted kind of company. And that's a big thing for an organization, especially when you're a group of you know, essentially basic scientists that have been working on the platform for the last few years to really sort of wrap our head around, well, what happens when you know you get to the clinic. So building that clinical capability is, is, is one of the things that we're working on right now. So that's like for us as a company.
Michelle Werner:But then, yeah, of course there's a lot of things happening in the macro environment, micro environment and, and, and certainly what I would say about that is you know we're tackling diseases that have incredible unmet medical need. You know we are everything that we do is going to transcend, you know, all of those different challenges that are happening in the macro environment, because guess what? Patients are still going to get diagnosed with these conditions and, unless we do something about it. Patients are still going to die with these conditions. So we got to focus on what we're doing. We've got to make sure that we have the capital in order to enable that to be possible, and then we really need to bring this technology forward. So those are the things that I would say is just trying to focus on the things that can be controlled right now and to, you know, focus on the needs of the people that we're aiming to serve, and that's what I wake up every single day looking to do.
Anna Rose Welch:Keep making medicines. Yeah, that's right.
Ben Comer:That is Michelle Werner, CEO at Alltrna. I'm Ben Comer.
Anna Rose Welch:And I'm Anna Rose Welch.
Ben Comer:And you've just listened to the Business of Biotech. Find us and subscribe anywhere you listen to podcasts and be sure to check out new weekly video casts of these conversations every Monday under the Business of Biotech tab at Life Science Leader. We'll see you next week and thank you for listening. Avantor is a leading life science tools company and global provider of mission-critical products and services to the life sciences and advanced technology industries. Avantor works side-by-side with customers at every step of the scientific journey to enable breakthroughs in medicine, healthcare and technology. Avantor's portfolio is used in virtually every stage of the most important research, development and production activities at more than 300,000 customer locations in 180 countries. For more information, visit avantor s Sciences. com or find them on LinkedIn, ex formerly Twitter and Facebook.
