Transformation in Trials
A podcast about the transformations in clinical trial. As life science companies are pressured to deliver novel drugs faster, data, processes, applications, roles and change itself is changing. We speak to people in the industry that experience these transformations up close and make sense of how the pressure can become a catalyst for transformation.
Transformation in Trials
From Lab to Patient: Why Vector Design Makes or Breaks Cell Therapies with Alan Griffith
Vectors are the unsung heroes of cell and gene therapy—molecular couriers that transport therapeutic genes into human cells to treat disease. But as Alan Griffith, Head of Global Operations at Vector Builder reveals, creating these sophisticated delivery vehicles is far more complex than most realize.
Drawing from over a decade of experience developing gene therapies before joining the CDMO sector, Griffith offers rare insight into what makes manufacturing these therapies so challenging. Vector design emerges as the critical yet underappreciated factor determining success or failure. "The fundamental sequence and vector composition itself is so fundamental to manufacturability," Griffith explains, noting how seemingly minor elements can dramatically impact production at scale. This knowledge has evolved painfully over the past decade, with clinical holds and manufacturing failures teaching hard lessons.
The relationship between therapy developers and contract manufacturers proves equally crucial. Rather than transactional exchanges, successful partnerships require deep collaboration and shared risk. "Working with a CDMO is like dancing with someone you don't know," Griffith observes, emphasizing how Vector Builder aims to understand diseases and vector compositions thoroughly rather than simply executing manufacturing orders.
Cost remains perhaps the greatest challenge facing cell and gene therapies. While small molecule drugs might be considered expensive at $10,000 per dose, that figure would be remarkably affordable for gene therapies. Strategies to address this include better vector design to reduce manufacturing failures, more targeted delivery requiring smaller doses, and challenging the "one-and-done" assumption that has proven more complex in reality as expression often diminishes over time.
Looking ahead, Griffith sees complementary roles for both viral vectors and emerging non-viral delivery systems like lipid nanoparticles and exosomes. He predicts viral vectors will continue to dominate certain applications for decades due to their unmatched effectiveness, while non-viral approaches may offer manufacturing advantages and potentially lower costs.
Cell and gene therapies are revolutionary treatments with vectors serving as "molecular couriers" that deliver genetic materials to target cells, but manufacturing these therapies presents significant challenges in scaling, cost, and regulatory compliance.
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Welcome to another episode of Transformation in Trials. I'm your host, Ivana Rosendahl. In this podcast, we explore how clinical trials are currently transforming so we can identify trends that can be further accelerated. We want to ensure that no patient has to wait for treatment and we get drugs to them as quickly as possible. Welcome to another episode of Transformation in Trials. Today, we're going to focus on bringing the cell and gene therapy sector forward, and in the studio with me I have Alan Griffith and Alan, maybe you could tell us a little bit more about what you're currently up to.
Speaker 2:Yeah, hi, ivana, nice to join you. Thanks for the opportunity to speak. Yeah, I'm now head of operations, global operations, at a company called Vector Builder. We are an end-to-end fully serviced CDMO. We've been in operation for about kind of 10 years now, with four or five years of that being as part of the CDMO. So, yeah, heading up the operations there currently. But, yeah, many years experience in cell and gene therapy been in various clinical trials, exposure to clinical trials so very happy to have a good discussion today.
Speaker 1:Very excited for having you here, and we'll get more into some of your great experiences later on in the episode. But for now, because a lot of what we'll be talking about is cell and gene therapy, could you give our listeners some of the context for what is a vector in cell and gene therapy?
Speaker 2:Yeah, sure, a couple of different ways to answer this, and I'll try and interlude between layman's terms and scientific technical terms as well to kind of accommodate any listeners. But yeah, vector is basically any vehicle used to deliver genetic material into target cells. So if you just think of it as a molecular courier, I suppose, or in other words, you know, a vector ferries genetic material into animal human cells with the idea that these genes then can cause an effect, maybe replenish a gene, gene replacement. There's CRISPRs now being put into these vectors as well that can also do gene editing. Basically, it's just a vehicle to get in and they're the ultimate vehicle we've seen over the last few years for selling gene therapy. They work really, really well. They come with challenges, of course, like manufacturing, which I'm sure we'll touch on during this conversation. But that's it. Yeah, in layman's terms, they're a delivery tool, taking the same idea as vaccines, but they're just empty and they're harmless and we're putting good stuff back in them in order to execute good stuff in a therapeutic sense.
Speaker 1:That's a great explanation, and now I'm seeing like a little fairy inside our bodies.
Speaker 2:Yeah, exactly, and obviously the whole field has been quite good because due to the COVID response of course. You know an mRNA and I think a big portion are attributable to the COVID response and how fast it was. You know we have a lot of people talking to us about how fast it was and what happened there. A lot of people don't realize because of the state of play of the cell and gene therapy field. It really allowed not a cold start but a reason to go straight in and actually utilize these vectors. You know the Oxford Biomedical one, for example, being a Chaddox, which is an adenovirus kind of ready to go. It's been tested at a small scale in research and development but you didn't have to start from scratch. So I think that's something that's nice to align, that the COVID response was very fast due to the really good state of play of cell and gene as well, among other things, of course, but that's always good remembering.
Speaker 1:Yes, absolutely. Well, I do want to talk more about being a cdmo in the cell and gene therapy space. It's the it's not an easy space to do manufacturing, and can you tell us more about the circumstances for this?
Speaker 2:yeah, yeah, sure, and having been a developer myself for the last 10, 12 years, um, I've really kind of changed my role here now, where you know you're you're trying to generate money and get money up from various uh you know investors, vcs, and going to board meetings to kind of beg for money and doing two or three projects and seeing a lot of failures, pitfalls and challenges. But at a cdmo here now, me personally I get to sit on and see hundreds of different client projects and utilize what I've learned in being a developer as being a developer on payroll now, to actually help guide them on their transition or their journey from research, preclinical into clinical. But like, basically, in the CDMO sense, that just simply means manufacturing, doing the CMC side of things for these wonderful vectors. And you know, it's very much a case of people doing either buy or build kind of models, where a lot of developers have the science. They have a fundamental decision to make very early Do we buy our own facility and kit it out, repurpose it and do our manufacturing ourselves? Or, you know, do we outsource it to a third party? And that's where the you know contract developers come in and we there's, you know, many hundreds of them around the world, a lot of them older than us. You know we're a little bit later to the party, but I do think that's okay because some of the challenges that they've had at the early stage, 10 years ago, might be running out of obsolete equipment, potentially staff retention. The whole field itself is very volatile, so it's moving and changing daily and weekly and so by being a little bit later to the party, I think you know Vector Builder, in this case as a CDMO, are a little bit at an advantage, which is great. But yeah, you know other challenges do exist because these products are so specialized to make and everyone thinks you just you select the CDMO, you know off you go and they'll manufacture it for you, but these things take so long to make and they're so expensive to make, all because you know the process equals the product in a lot of cases.
Speaker 2:Like that's something that's said now and again that you don't have these. You have these platforms, but it's a bit of a misnomer. The platform wording is a bit of a misnomer, I get it. It's a bit of a misnomer. The platform wording is a bit of a misnomer, I get it. It's used by marketers all around the world. It makes sense. But you know these therapies they're so individual, the fundamental sequence and the vector sequence itself is so fundamental to the manufacturability of it overall. And this is something that makes sense now.
Speaker 2:But you know, 10, 12 years ago we were like it can't be fully attributable to that and it's not fully, but it's definitely a huge portion. So that's a huge challenge because if you get client X and client Y coming to you with the same gene of interest, we can nearly guarantee that there's going to be certain elements of the vector design that are different, even though the gene of interest remains the same for treating the same disease. And those discrete differences and nuances will make the manufacturing different, especially at scale. You go to five liter scale initially for feasibility, 20, 50 liter and then obviously 200 liters where the majority of manufacturing is right now in the field, and obviously 2000 liters is possible. But there's very few people operating there and need to be there just now. Um, but they're kind of the kind of challenges in the area.
Speaker 2:Um, and just before I move on, I think one point I touched on the talent there talent retention.
Speaker 2:That's a huge challenge in the whole field because making these things is quite specific um, and you need a certain type of you know, technician, scientist, postdoc, whatever coming into the businesses to manufacture and having exposure making them. But not many people have been making them for too long, so it's very hard. It's very hard to get the talent and thankfully, at Vector Builder our model, because we are global and then we do a lot of manufacturing in Asia I think our staff retention is up around 94% and that really has a compounding effect every year because you're learning on top of that. And when people say that brain drain can happen, thankfully here it's not happening and I think that's just one challenge that we've overcome kind of silently, and we do like telling clients this as well, because I think it does make a big difference when you're trying to deliver first time on these things in my experience, having a like experienced staff for a prolonged duration when it comes to science is key to success.
Speaker 1:if there's too much turnover, you you start from scratch too much, and a lot about of it is institutional knowledge, like the know-how of making something work, so I understand what you're talking about. It's crucial.
Speaker 2:Yeah, and I'm glad you resonated on that part, because I know we talked about a good few things there. But the challenge is there. You know someone said it before it was like working with a CDMO was kind of like with dancing with someone you don't know and like it's quite intimate is like working with a cdmo is kind of like with dancing with someone you don't know, um, and like it's quite intimate. You have to partner with them. You have, you have to trust a stranger kind of thing, um, so what we're trying to do here, for example, is not be very transactional as in here's your, here's a product, please make it. It's like we want to really understand the disease. We want to understand what's inside it, what's the vector composition, what's the underlying sequence that really makes, uh, the transition between tech transfer into manufacturing and all that so much easier.
Speaker 2:You know the risk, the risk is there. It should be absorbed by both the CDMO and the sponsor, um, and I think that's, you know, the transactional side of things should be like getting removed where possible. You know we need, you need to trust us for what we need to do and we need to be better at fundamentally understanding the clients, and that's what we do and hence why I've come to vector builder now as a developer. We've got one or two more guys as well coming through. That can actually help with those conversations because you know you can pay lip service to these to people all around the world. But if you don't actually have, if you haven't been there done that, got the t-shirt, I mean it's easy to just. You know, talk is cheap and that's I think it's going to be a big differentiator for cdmos going forward.
Speaker 1:Yeah I'm I'm curious what? What is a good profile for hiring into the cdmo space? You mentioned, like several levels of technicians, phds, postdocs. Are there personal attributes? Are there scientific attributes that make you especially great at this space?
Speaker 2:Really really good question. I haven't been asked this before. Yeah, I mean like there is a bit of a problem, I think and I think a lot of CDMOs will disagree with me here, not in controversial, but you know, a lot of people work in a CDMO and I've been in working in a manufacturing group, I've managed a manufacturing team and they kind of, you know, the more qualified they are, the more they kind of get bored really quickly. So it's about that. Self-motivation is a big driver.
Speaker 2:You tend to get, you know, a lot more more numeration sometimes by being in a cmc role than you would necessarily if you're, you know, in a research role. But because that kind of comes with the territory of being a little bit more monotonous, it's a little bit more routine. You know you should be robotic in how you do things in order to comply to gmp compliance and all makes a lot of sense. But but when you're that person in the room doing the very important step and you're really not trying to mess it up, that's a lot of pressure. And then some people love the pressure, but then they get very bored of the pressure if they've manufactured loads of batches.
Speaker 2:So it's that kind of mentality of person that you look for that's going to to that understands that, rather than just maybe hiring people and letting them figure that out themselves and then kind of crossing your fingers hoping they don't leave, it's better to just to address it up front and then make sure that the company can facilitate learning in a different way or doing different tasks or different unit operations, that they can, you know, fluff up their skill set, make sure that they don't get, you know, refreshed and because a refreshed technician there makes a lot less mistakes and one of the biggest challenges in batch manufacturing is the failure rate you have one or two gaps in the gmp process and you have to, you know, tank the entire batch. That's where a lot of the cost comes as well with these things, because you have to allow for that happening because they're so complex, there's so many individual steps, you know.
Speaker 1:Yeah, that's. That's a good point, and I like that you bring forth self-motivation because for me also, whenever I have been hiring, looking for someone who understands well what I would like to achieve in this role is so-and-so, Not for myself, but for the company, for the product. They usually tend to ask longer and also build those bridges to other departments and improve the process.
Speaker 2:Exactly. I think it's a given that people will have the skill set. They'll have the quality, you know, goes back to one thing uh, you know the marketeers kind of try and get to do. I work with the marketeers sometimes because they're like give us the insight. And you know you can't really market quality because quality should just be given. Quality is a given that you're at a gmp standard and that's the benchmark and you don't deviate from that. So you, you can't really say, hey, our quality is better than this CDMO. Let's be honest, it's just a given, it's standard. Where the differentiator comes from is from, as we said, the staff making sure we invest in the right equipment, make sure that we are actually able to conduct the work in a faster and better way, and try and find efficiencies in other ways, but quality is just not compromised. Find, you know, efficiencies in other ways, but quality is just not compromised.
Speaker 1:It's not a marketing term that you should use. You know, yes, yes, but getting to that quality is actually not an easy thing to do.
Speaker 2:No, no, it's really not. It's difficult and it's. You know, a lot of clinical trials right now are on clinical hold because, um, not necessarily always quality events, but the quality events that have manifested by, maybe the underlying vector sequence or the vector design being putting the specification out of, out of kilter, or skewing it so much so that you do have a quality event. But that's the quality event against maybe the specification, not necessarily a safety quality event or an immunity. You know it's not dangerous to the patient, but you've still set a certain specification and then you haven't hit that. So therefore you have a deviation and you have to address that going forward, you know. So that's an important point as well.
Speaker 1:Well, alan, now you have had the luxury of observing, like different kinds of companies, their vectors. I'm curious how much do they have in common and how much is different? You, as a CDMO, how much knowledge base do you get to build seeing different products being manufactured?
Speaker 2:Yeah, yeah, yeah, it's a really good point. Look, there's commonalities, there's more things in common than there are differences between CDMOs, if I'm honest. And you know there's going to be regulatory requirements, robust quality control. You know scalability aspects, right equipment, the right people. But you know, I think one of the aspects that people don't realize is we're quite fungible. You know, I use the word fungible now because it's obviously quite in with the kids, because nfds and all of that.
Speaker 2:But that interchangeability or interconnectivity between these things, you know every. It's no point having a quote from us and a quote from another cdmo and been like oh, you know, we're using some fancy equipment. You know everyone uses a lot of the same suppliers, the same equipments, the sitevas of this world, the pauls of this world. You know everyone uses a lot of the same suppliers, the same equipments, the sitevas of this world, the pauls of this world. You know there's not many equipment suppliers and at the end of the day, you've got the top tier suppliers and you've got maybe top tier two and the tier two are actually just as good in places, but everyone likes going for the more expensive units.
Speaker 2:I mean, that's what we've invested in, um, but we're not going to sit here and say our equipment is way better than CDMOX, because I think that's where you know. That's something that I think clients it's important for them to know, because they're kind of hidden behind the veil of they don't know, they're not in their labs, they haven't got a window in. We try and show them and, instead of trying to say that we're we're better in certain ways, we just be very honest about that and say look where we, we don't worry about trying to look good with equipment. We try and look good regarding the process and how we deliver the process and execute. Um, because that's the usp for me, um, and then, yeah, I just think some sometimes there's a you know cdmos that have a track record that's amazing obviously you've got into clinical trials, you've manufactured these things a lot of times.
Speaker 2:That that's, that's great. And you know we're struggling in that regard. If I'm honest, I'm not struggling, but we don't have we don't have the track record. We're a bit slower to the table, like we're a bit late to the party, but that's OK because at the end of the day we will naturally learn from what we're delivering we're getting these products into patients now. From what we're delivering we're getting these products into patients now. Then you know we're doing what I think is a lot faster and a lot more cost friendly, which hopefully we can touch on as well.
Speaker 2:The affordability factor is very important going forward and that hopefully we're starting to catch up with some of the big players or the pioneers in the field. And I think that's where I think that observation kind of comes from. That you know, when I joined the cdmo I I actually thought that. You know, I was a previous developer client per se, and I'm like I wonder what equipment all these guys have and the more I've seen over the last two or three years. Everyone is pretty much the same thing and we're all anyone hears about a new disruptive technology coming. You know we'll always say I kind of want that because I don't want to be either left behind or we're starting to see publications or some of the key opinion leaders within the field now reporting on this equipment or reporting on these, you know, and machines to do assays and stuff. So that's quite important, I think, just to keep on top of it, keep the trends away, keep your, keep your antenna and tuned in for what's what's kind of coming out there. And in that regard, it's pretty much a parity across the board, which is good it should be.
Speaker 2:The client shouldn't be hoping they get the selection. The CDMO selection is a critical decision they have to make. They don't want to sit there and go. God, I really hope I didn't get that wrong. Chances are you should be okay, even if you go with somebody that doesn't, you know it's not as good as you thought they would maybe necessarily be, you know. And and then, final point on that, I just think, just to close, that part was the, I think, the biopharma report. From the global biopharma report in 2023, it was like 40 percent of developers are not happy with their cdmos, but none of them really cite the equipment or anything. It's all about how the interpersonality is how the?
Speaker 2:relationship like speed is not one thing, but the speed of conversation and diverge, going deeper into their project, listening to them. You know so that these are the things that the people you know 2,000 people you know surveys and report, and that's quite telling. 40%, that's that the people you know. 2,000 people, uh, you know surveys and report and that's quite telling. 40, that's quite high, you know, considering that there's a lot of people just not happy with their cdmos, and then I'm hoping, vector builder, we can maybe come in and if people are not happy, they want to maybe test us out. Yes, we don't have to track record, but you're like you get you. They're in a position now to make a change and we want to maybe just be there for them Because, at the end of the day, we don't want them to slow down and getting these wonderful products to patients. Why would we? You know?
Speaker 1:Absolutely and again, like the human factor there in collaboration between a sponsor and partner, also, in my experience is the most important part yes, yeah, exactly it is. I'm curious. Well, so what are some of the challenges of actually manufacturing these vectors, because I assume going from the development stage to actually being able to produce them, that is likely not an easy thing to do.
Speaker 2:No, no, it's not. Yeah, it's a kind of stack question. There are a few different ways I could answer it, so I'll try my best. But the way I look at it and something I touched on in the last answer was you know that vector design element being so pivotal to manufacturability. And you know, when we were going into clinical trials, when we, you know, build up the business spinning out of UCL years ago, we didn't really know what sequences were clinically compliant, were acceptable.
Speaker 2:You know, you have this huge knowledge now, that ampicillin-based backbones are not the way forward. They are. You know there's probably not too much wrong with them. But there is this hyper like beta-lactam hypersensitivity in the field that if you do manufacture a plasmid with ampicillin, there is a worry that there's trace elements of it coming through that could find its way into a patient and I know that's a step or two above where the virus is manufactured. You know we need plasmid precursor material to make the virus, but you still have trace elements and because it's hypersensitive, you might have that coming through. So we didn't know any of that in the first. You know 10, 12 years of making it. It was like we just didn't really care what backbone exists, we're the fastest way to clone it. It's in an ampicillin backbone, let's just go. Whereas now, I'll guarantee you there's not one developer over the last maybe four or five years would ever consider bringing an ampicillin based backbone into the clinic, and even if it is upstream from manufacturing the virus, because if you can change it to a can of mycin, for example, why not change it at the very, very early stage, even when your researchers are coming up with the proof of concept data? Just get in the habit of doing that and then you've got one less thing to worry about during your clinical translation, because that could impact your manufacturing. It impact the quality control, the purities, all of that. Empty versus full ratios, all of these things. So, yeah, I don't want to harp on too much about the vector design, but I mean, there was a nature paper there last week, uh, vivian marks, and she had actually reached out to two or three people at vector builder and all the other cdmos and people who are good vector, you know, uh, key opinion leaders.
Speaker 2:Everyone now is kind of coming around to the fact that, wow, this is really pivotal. It determines therapeutic efficacy, it determines safety, determines scalability. These discrete elements, a handful of bases, a handful of nucleotides within the sequence can have profound effects as they get amplified up beyond certain scales. Um, we didn't even know that, of course, 10 years ago. I always go back to the now versus then um, so that's why you're saying you know how we, at least now, can consult our clients coming through that. Here's two or three things that you can do now as of today that will at least help you when it comes to manufacturing challenges.
Speaker 2:Later, a lot of the same challenges regarding chromatography development, process development. They still exist, but you've released, eradicated three or four big problems when it comes to compliance, safety and scalability because of the way you've designed the vector, and that's a huge win. It's a huge win and we didn't have that win 10 years ago. So I think that's important for people to understand as well that no vector design we talked about vectors earlier. It's that vector design instead of just maybe an off-the-shelf vector. You really take time scrutinizing it, interrogating every single base within there, and we can do a lot of that work now as well. I think we're the only um cdmo that well, not the only cdmo, but, as far as I know, the only cdmo at a certain hour size that has the cro part division of the business. So we've been a very successful cro company for years and we've got a CDMO now. So we've got something like 4,500 clients.
Speaker 2:I do see that from our slides that they're even if a small percentage of those transition into clinical trials, that's still hundreds of potential clients that will come to us that need to transition their vector. So we're able to have that need to transition their vector, so we're able to have that vector conversation with them early as they're ordering their research preps, as they're ordering their research materials, and they're like I'm not worried about clinical and I'm like you know, well, we are. Yes, I know, I know you're not, but that's a bit of here. Why not just make these two or three changes? We won't charge you any differently for changing them, and then you'll be kind of ready.
Speaker 2:And that sounds like you know we've been condescending, but we're not, because it really helps us as well, because we don't want them to spend two years doing proof of concept. And then they're like haha, eureka, I have the vector I want here. Vector builder, can you please make it? And then we do the assessment. Vector assessment takes an hour or two to look at it and and we're like we already know, after making a million vectors at this stage, that this is not manufacturable and you could have had that decision and now you have to go back and maybe repeat some of the work. So that's the big, I think, role that CDMOs and the knowledge transfer has regarding boosting manufacturing success, if that makes sense, Absolutely Like bringing that expertise to the earlier stages of research.
Speaker 1:It makes life much easier downstream.
Speaker 2:Big time, yeah, and there's other companies looking at the in silico models where you know you can look at the in silico side of the sequence tertiary structure, snapback genomes, formation of those. I mean that's all great, but I mean the AI and machine learning that's obviously coming at full pace and we're trying to keep our antenna aware of those. But there's an empirical part of that as well. We have huge process development labs and capabilities where we could do the small scale experiments at one liter, five liter, and then you are able to screen like a doe type situation where you're doing loads of different iterations of the vector design, because I think a lot of the ai tools that you know some of these companies now have set up and they're like you know, make a better vector design using our ai tool.
Speaker 2:I'm like but have they got the capability to do the empirical testing? Because, fundamentally, the ai tool, nine times out out of 10, it could be excellent, but then one time out of 10, it's not, and then you'll never, as a developer, be able to get that time back. That's a lost time. So, parallel tracking it with the AI tool but then doing some empirical work, that's part of our Clinivec service. It's a term I've coined working at Vector Builder, but Clinivec is a clinical compliant vector build clinical compliant vector, and then it's based on the three pillars I've always mentioned the manufacturing, the safety and scalability. So that's hopefully.
Speaker 2:We're starting to see people inquiring about that now, because the problem with it is it costs more money upfront, whereas they might have said we've only budgeted for one clinical preclinical candidate and you have to try and convince them, hey, you should really look at at least 20, 30 preclinical candidates. I know that sounds crazy. I know that sounds like loads more work, but that's a really low cost burden at that early stage where you don't have GMP involved, you don't have large amounts of virus to be made. That's the iterate. You know. Do iteration and really focus on it. The amount of clients that said, it makes total sense, but I've told my investors I need to pick one within a month and you're like well, you are putting yourself at a disadvantage there, but we're not going to tell those people to go away. Of course, we're going to try and help them as fast as we can, so that's important yeah, it's a good point about the scientific process in general.
Speaker 1:Like we have, it's cheaper to experiment earlier and it gets more and more expensive the later experiment.
Speaker 2:Yeah but unfortunately we talk to them well after they've had the conversation with the investors. But that's good. That's good because we've some research clients now and they're like hey, alan, um, you know I work very closely with andrew alcock, their previous uh, oxford biomedic, uh, gentleman um, and they are asking us to attend some of their investor meetings because they're like can you please just talk about all that manufacturing cmc stuff you're talking about and why it's important? And they almost use us to convince the powers that be to actually spend more time up front and do better development. And and we think that's great because building the relationship it's allowing us, you know, exposure in that realm and it's it's like it's the right thing to do, because there's no point just picking one needle in a haystack and then hoping for the best.
Speaker 2:To be honest, that's where a lot of cdmos get a bad reputation because they actually haven't put that stage gate in place. They've kind of just said, yeah, you come to us and we'll manufacture it for you, and not appreciating the complexity of the underlying vector design. And then they're like we can't deliver, we can't manufacture it, and then they're tainted forever that the CDMO can't make our bloody thing and you're like you have come about it the wrong way. So I'm not saying we're going to be totally avoiding failures, but we're at least giving ourselves a better shot and a better chance at success and I think we're all quite excited about where it's going for the next few years, with some of our big orders coming through for clinical trial orders, you know.
Speaker 1:That is exciting. I do want to circle back to the price part, because that's the thing in cell and gene therapy is the price. How do you see that it could become more affordable?
Speaker 2:Yeah, tough question. You weren't letting me play with that one. At the end of the day, it's the million dollar question or it's the multi-million dollar question. Let's be honest, this question has been around as long as the field had that resurgence 15, 20 years ago. I don't know the best way to answer it, but I'll try and think about a few different ways.
Speaker 2:Comes back to what I was saying. We have that clinic service there. Now you spend that money up front and fundamentally then you're not spending money on failed batches later. I'd rather spend 10k now than spend 100k on and repeating another batch. So we we're we're CleanEvec to really bring the affordability factor down. And okay, that sounds like we're spending more money upfront, of course, but there is a payoff kind of later. So obviously the affordability hinges on these kinds of efficiencies.
Speaker 2:Other way to do it is collaboration. A lot of people were always very competitive. Right now You're seeing a lot of people divesting. A lot of people are always very competitive. Right now you're seeing a lot of people divesting. A lot of people collaborating and doing strategic partnerships with people and to really not not do everything all under one roof, because by the time they develop it themselves and then roll it out. They've spent millions of pounds themselves and the client could be gone. So I think it's about leveraging who's available, who has what. You know. If you're not really good at fill and finish, maybe considering outsourcing it until you become really competent at it, and these are the type things that you can do, I think, from a an operational perspective, and that's kind of my, my bag, of course, um, but yeah, this question has been around the boardrooms for for years and it's heavily nuanced, unfortunately.
Speaker 2:But, um, kind of a simple example I always say to this is for the kind of lay people or anyone who's who's reading or listening. But you know, 10k, 10, 10 000 is obviously a dose for maybe small molecules would be considered very high. Well, you know, historically, whereas 10k for a gene replacement therapy is considered very, very cheap and someone thinks you'll have to get your head checked. So we're trying to be like small molecules was, you know, nabs, you know 20, 30 years ago. We're trying to be the same in that, you know, work the same way, get us up to that kind of level and but that price is probably never going to be really achievable and maybe for certain diseases where the dose requirements a lot less. Fair enough, but all things being equal, you know, we just have to kind of accept that it is really expensive. And then the fact that they are, and hopefully going to be more life-changing, better, uh, more long term.
Speaker 2:There's a huge durability factor. Um, it's a bit of a misnomer, I think. I'd like to come back to some of the misnomers, maybe towards the end of the, the podcast. But, and you know, one and done, people say street at once and then that's it. We were hoping that was the case 10 years ago, but time has shown now that there is a kind of a tailing off of expression and this durability factor is not really quite there. So that was always going to be our angle to say it's expensive but it's a one and done. Yeah, that's now coming back into focus, where only in certain circumstances, only in certain cases that that holds true. So that'll be interesting now to see how we all, everyone in the field, manages the economics around that, you know. Hopefully that makes sense yes, absolutely.
Speaker 1:I do want to hear more about the misnomers really right now you want to hear I I'm.
Speaker 2:This is the thing as well. I was hoping I've chose. I'll try and choose two or three that I've. Um, I think people will agree with me because I think, at the end of the day, here we're talking and I'm trying to be not as subjective as possible everyone has a subjective experience but I'm really just trying to talk about you know what is misnomers? I think in the field they can really misalign expectations because for that one thing talking to investors one and done, one and done If you actually explain to them what, the way I've done it there, that okay.
Speaker 2:Now we know, 10 years later, we've learned from all the clinical trials ongoing. There's a better, there's a public misunderstanding in place. So therefore, we want to address that with you as well. And so you have to try. And you know, as the field advances, look at you know better education, better clinical data and understanding this data is really important. So that's a misnomer I think is very important.
Speaker 2:And another one is the more vector there is, the better of efficacy you have. As in more vector, more this thing cures you, the more of it you have in place, the better off you'll be. Now, higher vector doses, the way they work does not always mean better results, you know excessive vectors and sometimes can lead then to immune responses, toxicity, off target effects. These are three big issues in the entire field. So more is not better and and you can, you can use that in many circumstances, you know. So yeah, I just think that one time treatment is something that is there Again. Some investors will probably kill me for saying it, but I think it's just that's. It's our responsibility to make sure that it's very holistic. The understanding around that and removing some of these misnomers is totally fine, because I think they can be replaced with better solutions and it's not a case of, oh, we're all screwed, it's not about that. It's just about we know stuff now that we didn't know then. And let's remove some of these misnomers, because I think that will help avoid misaligned expectations.
Speaker 2:And that's our clients as well. You know the clients come to us and say, yeah, but I was talking to someone else and they said I could do it in 50 liters. They're like what, what design is it? I haven't talked to them about the design yet. Okay For them to tell you that you're a hundred percent going to get 10 E13 in a 50 liter bioreactor, without knowing your vector design or your sequence. Well, honestly, they're. They're just trying to get you, lure you in. Let's be honest, it's a good sales tactic. It works. And, let's be honest, there's a 50% chance he's right or he, he or she is right, a 50% chance they're wrong. I'm we're just really trying to tackle it from a realistic perspective, that that you can't say that, um, and be 100 true and that's, that's okay. Um, we're here to help with that understanding, yeah absolutely, and I think those were great points.
Speaker 1:And also, this is just the scientific process. We learn more and then some of the things we're assuming in the past no longer hold true, and then we need to adjust our expectations.
Speaker 2:Yeah, exactly. Every idea is a bad idea until it's a good idea. Exactly yeah.
Speaker 1:Eventually, we'll figure out the price. One too, we've given enough.
Speaker 2:It is going to be interesting to see. You know people are focusing on routes of administration. So you try more, you know, more targeted routes of administration because if you go more controlled and less systemic you can bring that dose way down because it'll be compartmentalized in a certain tissue, like the brain is great for that due to the blood brain barrier. The eye was obviously great because it's got, you know, immune privileged and it's a, you know, a perfect control. You've got a left and right control. That's why a lot of ocular gene therapy companies, ourselves included really set up at the start because it was a really good way to keep the dose down. The manufacturing is quite, you know, mediocre, as in the cost, and allows you to kind of get that familiarity, get that experience, get that competency, get the investors excited and then you can maybe diversify your portfolio. Look at cns diseases, look at other um, other therapy or other disease pathologies as well. So, and that's that's kind of important you know, if you're going into cell and gene therapy, you manufacturing is not your only challenge. You know you, you need to actually understand the disease inside out, whereas the problem, I think, in the field a lot of cell and gene therapy experts. They're not pathologists, they're not clinicians. So you really have to help with that conversation early and I honestly think if you have those better conversations early, it can probably save you a lot of time, money and effort later on, and that's that's something that kind of makes sense.
Speaker 2:But I don't. I don't think the systems or the infrastructure in the field are really set up for that. Um, it's getting better. There's bioform, uh, you know, there's uh groups that are set up, there's um lobbyists now and and there's all of these things coming together quite nicely to kind of create these systems or these infrastructures that can allow people, the right people, to have the right conversation early as possible. That's going to be fundamental to the cost coming down as well. Sorry not to go back on that, but you know you touched on it again there and I was just continuing the same thought process.
Speaker 1:It's an interesting point. We talked a lot about, like, the initial stages when it comes to research and manufacturing. What about the regulatory approvals for cell and gene therapies? What are some of the challenges and developments we're seeing in that space?
Speaker 2:Yeah, yeah, great. This is a great question because we're talking a lot about manufacturing, talking a lot about cost, but the regulatory landscape has changed, usually over the last decade as well. And you know the agencies. They're all learning pretty much the same, as these developers and even the CDMOs. You know, my recommendation there is you know, don't assume what you heard in, maybe from an agency meeting five years ago. Things could have changed there. You know it's really good at a lot of our cell and gene therapy conferences. Things could have changed there. You know it's really good at a lot of our cell and gene therapy conferences.
Speaker 2:You know the likes of peter marx from the fda and all of these kind of speakers and good communicators um, they're not treating it like a black box. They're actually getting in and amongst the people and trying to tell us that, hey look, we thought this was changing and we weren't usually worried about this. Now we're starting to be worried, as in like aav integration, for example, we always like, no, aav doesn't integrate. That's one of the challenges of it. It remains epizomally. But at the same time now we're starting to see that, no, it actually does integrate at low frequency, fair enough, in certain parts of the host genome.
Speaker 2:So the question then is does that, is that okay? Is that bad? Is that good? Is that you know dangerous? And then, like the agencies are like you tell us, like you know, if you think it's safe, show us and demonstrate it that it's safe. So I think that's what I've learned a lot from the regulatory kind of landscape over the last few years, that it's changed. And you know, be comfortable with being uncomfortable a little bit. I'm trying not to use too many cliches, but you know a lot of people think they're trying to catch us out, but they're not. They really want you to succeed because there's room at the table for everybody and they really they want to, like any human being, they want to do less work. They want to be able to set up these kind of more like conventional frameworks that allows people to move through right the clinical phases much faster. They. They get no advantage by it being slower. They it's just giving no one, does you know?
Speaker 1:Well, during our pre-call you mentioned that it's been a difficult year for this the Ceylon June therapy space last year. Can you elaborate more on what made it a difficult year?
Speaker 2:Yeah, yeah, sure, a few different ways. I suppose the challenging year is obviously, you know, the investment money. Money was drying up a lot. I think a lot of people were cash rich over the last few years and you know a bit of on the boom. We're starting to see a bit of a recoil, naturally because, as I said before, the clinical trials some of them, are on hold and they're on hold with without really a clear way forward as in now. You don't, you don't necessarily mind the clinical hold now and again because you can. You've found the root cause, you know how to do it. The only pain within the entire business is that it's delayed everyone by three to six months. But you actually have an answer, you have a way forward.
Speaker 2:Some of these now clinical trials they don't actually have a way forward, so they're having to go back to the drawing board and actually think about things a bit deeply. So that clearly translates into investor sentiment and what's actually like. These guys are great scientists but they're not really great at developing these things into scalable manufacturing modalities, you know, and when you think about it, it's not it's a criticism, but it's not a criticism at an emotional level or a personal level. It's like I think the investors are just wising up to the fact that oh well, uh, it's a lot more trickier than we thought. Just because we had two or three success stories, as I I said, in a certain disease area that could be quite applicable or amenable to certain gene therapy, it kind of biases everyone else's opinion that, hey, gene therapy is easy and I'm sure in some cases it is. So I think that's then been the reason for the challenging year, that the money has dried up.
Speaker 2:But having been at JP Morgan this year, there is kind of now that resurgence again, conversations happening. We're talking about things like the Clinivex, like the equipment. Disruptive technology users are finally catching up with us and quality control groups and quality control companies and the guys that manufacture these wonderful machines. They're starting to really come into their own now, and that means better characterization of the virus earlier in the development lifecycle and then that means you can make way better decisions earlier without going and hitting those clinical trial roadblocks. So I think the investors are also aware of that, that oh, it's not just a dead rubber.
Speaker 2:The whole field hasn't come to an abrupt stop. Yes, it's at a bit of a plateau, but there's a bunch of smart people trying to figure out ways to counteract the problems that may arise in clinical trials, manufacturing just being one of them, um. So yeah, um, hopefully that makes sense. And then I think, yeah, the uh, the orders you can see it translate the orders just come down low for the last year or two and again, look at the end of the day, these, a lot of these high profile projects have failed, um, but there's always going to be either new products coming into development or I actually think there'll be a huge resurrection situation where, you know, one or two companies can get the clinical trials, they meet the roadblock and they realize we missed the giant.
Speaker 2:We made a big boo-boo here. We, we missed the point here. That could have saved us this hassle, but unfortunately we need to go all the way back to phase one and repeat the work. I actually think what may happen is you'll get a lot of developers or people coming in, or maybe like the biosimilars type mentality, where they come in and say the only thing that failed, that caused that wonderful drug or therapeutic to fail, was x. We can fix that now and we've the money to bring that all the way through. So you'll, you might see these resurrection campaigns or these resurrection companies setting up where we'll buy the rights for that, that, that project off you, or that indication that if you go forward and I think that's that's still the great white hope of like the investor money, that's good bang for your buck. That's where you know confidence is starting to creep up.
Speaker 1:Yeah yeah, and it's because it's still a relatively new space. We do need those examples where, there we go, we've actually figured out what was wrong and now we can do it all the way exactly. That'll be helpful, yeah, yeah. Well, alan, I would like to learn more about your journey into this space. How did you end up in this helen gene therapy area?
Speaker 2:yeah sure. Um, I went to the shop one day and then bought some eggs, yeah I actually fell out of love with science big time after my phd.
Speaker 2:Um, I was doing it with a wonderful PI and a wonderful organization, the National Institute of Cellular Biotechnology in Dublin City University. However, it was just kind of partially funded in different ways by Big Pharma. I wasn't allowed to really talk too much about what some of the findings were. I felt like I was doing a lot of work, kind of maybe I'll just get put in a filing cabinet and logged away and not actually go anywhere. So I wasn't really too sure what I want to do next. All I knew is I had viral genetics background. I'd done bioprocessing and phenotype mapping for my PhD, which is basically utilizing viral genetics, and so I wasn't necessarily in gene and cell therapy per se. It was a lot of the same vectors and materials that's used in cell and gene, but I wasn't actually in the cell and gene therapy sector.
Speaker 2:After my PhD I decided to go to UCL and apply for a role there working on Professor Robin Allen Ali's group very successful professor there who built out and spun out a company called Athena Vision which went on to be Mira GTX out of UCL. And that was a hell of a journey because I was like the fourth employee there. We literally built up the company within a few years. We built our own manufacturing again. Will we do that again? Not sure, but we definitely decided to build our own and control our own destiny kind of thing. But that's pretty much what happened. The rest is history, as they say, I went up to director level there and then went to become vice president of research at another startup AAB company in London, went to a short stint in the Nordics to work on adenoviruses as chief development officer there and subsequently, yeah, money kind of runs out and decisions to work on adenoviruses as chief development officer there, um, and subsequently, yeah, money, money kind of runs out and decisions.
Speaker 2:And you start reflecting then, over the last two years, where am I? Okay? Uh, you know, um, begging board members and investors for money just to do this work that I don't. They're asking me are you sure it's going to work? I'm like really, me and the team, we don't, we don't, we don't bloody know. Um, it's research, yeah, yeah, so that that stress kind of takes its toll and obviously trying to start a family and stuff.
Speaker 2:And then I decided I use vector builder for many years, um, as a useful service provider and had the right conversation with the chief operating officer there at a conference, told him pretty much the exact story I told you now and he's like come here, I think there's a job here, we can work on this, and you being on like a developer on payroll would really help facilitate. So I consulted for a few months and then they've asked me to join full-time as head of operations now and it's great. It's a global company. I get to work in China, I get to work in Asia, japan, america, all of that. We've sites all over the world. So that's kind of how I'm in front of you today, because obviously that connection there, um, and obviously you're you're a good relationship with you already.
Speaker 2:So, um, yeah, but the journey was driven by passion for getting into patients, because I think this was the new area, this was an emerging area of biotech that was growing 10 this is 12 years ago. Um, that postdoc. And then you're like I was a postdoc for a few months and decided I want to work in this startup company. I can't pay you any more, alan, but I don't want to stay and let's see where it gets us. And here we are, you know, 12 years later, um, and it's been a hell of a journey and it's great and I'm so proud to be part of it. I'm delighted how it was and there's so many learnings as well, which probably won't go into.
Speaker 2:But there's a lot of things I do differently. There's decisions we made and you're like I can't believe we wasted so much money doing an nhp study when it was the wrong thing to do. But that's why I'm here now. I'm here so I can hopefully tell at least that one or two of our clients listen to the same kind of pitfalls that we had. That's good use of my time, because that's really helping bring them forward, bringing the field forward and reducing the value of debt. You know the value of debt. A lot of products go in there. None of them come out the back end. If we can reduce the value of debt, I'll be super happy and that's what drives me forward. That's the passion, yeah.
Speaker 1:I completely relate to that, but also you got so many different perspectives perspectives on this field from different areas that that makes you an amazing partner for you can quote me.
Speaker 2:Yeah, no, but yeah, no, it's good, it's been. It's been a good journey and I'm lucky, I'm looking forward to the future. At the end of the day, there's none of this. I think the stagnancy even at last year was quite challenging as we touched on like it still has the ability to go this way, and now you've got non-viral gene therapy coming into its own. You know we've just invested in a brand new mrna lmp facility.
Speaker 2:Lmps exosomes, these non-viral vectors. So a vector again we're talking about, it's a vehicle. There's now non-viral vectors, which always existed, but they're really coming into their own over the last two or three years. So it'd be interesting to see how viral vector versus non-viral vector, how they stack up against each other. And you know viruses where they were, I wouldn't even. You know a lot of people say I never use anything other than the virus. But we're seeing now that some of these viruses don't like being manufactured, regardless of how, how you design them as well. So that's another thing. Just because we design them well at Vector Builder doesn't mean they're 100% going to work, and some of these things just don't like being made. You know, because you have to make them in these mammalian systems or bacterial systems and you're putting viral pieces inside a bacteria and the bacteria is like, hey, I don't like what you're trying to do.
Speaker 1:I don't want this yeah trying to do.
Speaker 2:I don't want to.
Speaker 1:Yeah, that's interesting. It's definitely a field that I'm interested in keeping an eye out for and seeing how it evolves. Yeah, it'd be exciting.
Speaker 2:Yeah, and the money. I think we talked on about the investors a lot there and didn't actually mean to do that, but I think they're quite interested as well because that cost and affordability. You know viral vectors will always have a place because they work so well. They're not going to be eradicated or become obsolete, but it's just a case of some of these new developers coming through with these new indications or disease targeting therapies. There is a chance that the cost could come way down because they're a lot easier to synthetically make.
Speaker 2:You're not waiting around for the virus to do its assembly process. You know it's. It's a very natural phenomenon that happens, and if you can synthesize them using chemistry and using you know there's 3d printing of molecules going on I mean that could bring the costs kind of way down. And then maybe we find ourselves in this place where the majority of people are using non-viral. However, I firmly believe that they will be using viral vectors for the next 100 years because they're just too good in certain diseases in certain contexts that they couldn't be eradicated. So we need to keep fighting on both fronts, basically.
Speaker 1:Yes, and this episode turned out to be excellent investor advice, because it's both about looking out for the people who have failed and then try again. Invest in those, and also don't forget about the viral vectors.
Speaker 2:Exactly.
Speaker 1:Well, alan, as we start rounding off, we always ask our guests the same question. In the end, if I was to give you the transformation trials magic wand that can change one thing in the life sciences industry, what would you wish to change that?
Speaker 2:can change one thing in the biosciences industry. What would you wish to change? Well, yeah, so I'll try not to be greedy here because I was like I had a senior previous episode and I knew that might be a question here. But obviously the cost. I think that just goes without saying. Everyone wants the cost to come down. But my magic wand, I'll save it for, I think, more accessible QC. That is harmful because the quality control is always lagging behind, and I don't think this is the number one thing that needs to change. It's just if I had my magic wand.
Speaker 2:Much pain, quality control and characterizing our viruses while making them has put the CMC groups and the manufacturing groups in a disadvantage in going into regulatory meetings. You get asked, asked what's going on here, and you're like it's. This qc method is the first time it's ever been used to characterize this virus. Um, whereas now a lot more data out there. Some of these viruses, not only do they not like being manufactured, they don't like being tested and assayed and assessed, and so I kind of feel like that.
Speaker 2:I'd love that where everyone, all cs, all the clients, are all working in a similar kind of fashion that we've, you know, that harmonization of quality control. I'd really advocate for that because I think enhancing that will really help not only us deliver manufacturing and all of the things I've said, but also the regulatory side of things, which is what we're saying. It makes regulatory guys assess the information so much easier because they're like, well, everyone's using more or less the same assays here. There's like 16, 17 release assays. We're seeing a lot of them using the same. This is great because now we're starting to see, you know, structures forming, trends forming. We can trend the data, you know. I think that's quite important and going forward. But obviously there's other things that we change. But that's what I'd really find that would really help us right now and the field yeah, I.
Speaker 1:I love your response also, because this is something we can actually do something about yeah, yeah, yeah, exactly yeah.
Speaker 2:Yeah, it's very doable because a lot of people think of the qc side of things a little bit as an afterthought, and they have. I think it's getting better now. But, as I said, you know, cmc the second C in C stands for controls, and controls means QC. Everyone thinks CMC is manufacturing, but it's like no, it's the quality control built into the manufacturing and they have to go together. Unfortunately, over the last decade the manufacturing has improved a hell of a lot and QC has kind of stayed around the same and that that needs to change. And you know we're doing a lot of work on that in Vector Builder and I'm sure other CDMOs are as well. And but yeah, I think that's a big focus for us now going into our you know, newer initiatives around.
Speaker 2:You know you have to spend that money in that area and you're kind of like what if the client is very happy to use a very older kind of assay or methodology?
Speaker 2:And you're like we've just developed, spent millions developing these wonderful qc but they're not ready to hear the conversation yet. That's a risk. But and someone needs to make the step, someone needs to take the step and we are trying to do it and we're not going to go alone. We're trying to align with certain collaborators like test the beck and these companies in the uk, uh, pebble biosystems. They've got these wonderful organs on on a rig that you can actually dose the aavs, for example, on it and you get like liver and kidney readouts without actually having to go into animals. So therefore, your development costs come way down because you're not spending money on animals and it's also helping the three r's you know know refine, replace and replace. So I think that's very important as well. There's an aspect of that that we're working on and we're not. We're trying to be innovative in that space rather than just keeping the status quo, you know.
Speaker 1:That's really cool, also like for actually scaling the manufacturing, getting the QC right from the beginning. I bet that also makes a difference there. Exactly, I love your answer there. Thank you, no worries. Yeah Well, alan, if my listeners have follow-up questions and want to get in touch with you or Vector Builder, where should they reach out?
Speaker 2:Yeah, sure, I'll, obviously at Vector Builder, but get me on LinkedIn or whatever. I'm very happy. As I said, I've consulted before as well. Generally I don't I'm not a consultant that charges people. I like just helping the field because I'd want people, because generally by having a conversation with someone it works both ways. I end up gathering information or learning something from them as well, and that's like that's how we kind of need to work a little bit more as a collaborative. Like co-creation is something that kind of gets mentioned a lot as well.
Speaker 2:But you know that mentality shift I think is important now and you know it used to be very tight-lipped and you know ip protection and I get all of that. But there hasn't been many people fighting each other on ip and stuff in the cell and gene therapy space as a you know, when you think of biosimilars and you think of those other areas. So I think people are wanting we should actually just advocate for that a little bit more together. But, um, so yeah, but if anyone wants to reach out to me and have any discussion on anything I've talked about, free for conversation, love to have a coffee, whatever, um, but yeah, linkedin, um, my vector builder, uh, email. I give it to you as well, ivana. You can get get grab me there, so yeah.
Speaker 1:Awesome. Well, thank you so much, Ivan. This has been a great conversation.
Speaker 2:Yeah, amazing. Thanks for having me, Ivan. I really, really, really enjoyed it.
Speaker 1:Thanks very much. You're listening to Transformation in Trials. If you have a suggestion for a guest for our show, reach out to Sam Parnell or Ivana Rosendahl on LinkedIn. You can find more episodes on Apple Podcasts, spotify, google Podcasts or in any other player. Remember to subscribe and get the episodes hot off the editor.
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