Good morning, and welcome to the Codexis ECO Synthesis Virtual KOL event. At this time, all participants are in a listen-only mode. A question and answer session will follow the formal presentations. If you'd like to submit a question, you may do so by using the Q&A text box at the bottom of the webcast player or by emailing your questions to questions@LifeSci Advisors.com. As a reminder, this call is being recorded, and a replay will be made available on the Codexis website following the conclusion of the event. On today's call are Dr. Stephen Dilly, Codexis President and Chief Executive Officer, Kevin Norrett, Codexis Chief Operating Officer, Stefan Lutz, Codexis SVP of Research, as well as guest Dr. John Maraganore and Dr. David Butler. During this call, management will be making a number of forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, including statements regarding our projected cash runway to fund plan operations and our expectations for the supply and demand trajectories for oligonucleotide therapeutics, the evolving oligonucleotide manufacturing landscape, the potential for fully enzymatic oligonucleotide manufacturing technologies to improvements in patient outcomes and sustainability metrics. The anticipated improvements in speed, product purity, yield, and energy efficiency of fully enzymatic manufacturing process relative to SPOS, LPOS, and ligation, and the future regulatory framework applicable to enzymatic synthesis, as well as our expectations regarding the successful execution and commercialization of our ECO Synthesis platform, including those regarding our product roadmap, the platform's potential to drive innovation in oligonucleotide therapeutic manufacturing, RNAi market segmentation, and the anticipated customer base for the platform, potential benefits of our dsRNA ligase, and our expected timeline for achieving key development, pre-commercial, and commercial milestones. To the extent that statements contained in this call are not descriptions of historical facts regarding Codexis, they are forward-looking statements reflecting the beliefs and expectations of management as of the statement date, December 8th, 2023. You should not place undue reliance on these forward-looking statements because they involve known and unknown risks, uncertainties, and other factors that are, in some cases, beyond Codexis' control and that could materially affect actual results. Additional information about factors that could materially affect actual results can be found in Codexis' filings with the Securities and Exchange Commission. Codexis expressly disclaims any intent or obligation to update these forward-looking statements except as required by law. Finally, the guest thought leaders today are presenting on behalf of Codexis but are expressing their own independent perspectives as experts in the space. I'll now turn the call over to Stephen Dilly. Thank you, Tara. Good morning, everyone. I'm Stephen Dilly, President and CEO of Codexis, and I'd like to welcome you to our enzyme-catalyzed oligonucleotide synthesis, or Ecosynthesis, KOL event. As we approach the end of the year, we're thrilled to be welcoming some of the leading voices in RNAi therapeutic development and manufacturing into the conversation around our exciting ECO Synthesis platform. We're joined today by Doctors Maraganore and David Butler. Dr. Maraganore pioneered the translation of RNAi from a laboratory tool into an entirely new class of medicines. He's the founder and former chief executive officer of Alnylam Pharmaceuticals, where he built and led the company from an early research platform through the global approval and commercialization of the first five RNAi therapeutics. Today, Dr. Maraganore serves as an advisor to multiple biotechnology companies, and he recently joined the Codexis Strategic Advisory Board as our inaugural external member. Another prominent expert in the space, Dr. Butler, is currently Chief Technology Officer of Hongene Biotech Corporation, a fully integrated supplier of raw materials and CDMO services to customers in the RNA therapeutic space. Previously, he drove the platform discovery and development of oligonucleotide therapeutics across multiple biotechnology organizations and spent time as a principal scientist at Alnylam. There, his work centered on developing early lipid nanoparticle technologies for siRNA delivery. These two individuals have built their careers around shaping the siRNA market as it looks today. We're honored to have such influential figures joining us for this event, and we believe their willingness to participate speaks volumes about the importance of this topic. Oh, and if I click in the right place. There we go. During today's program, we'll hear our KOLs' perspectives on the anticipated demand trajectory for RNAi therapeutics, the current manufacturing landscape, and the role for an enzymatic approach like our ECO Synthesis platform. The technology was born out of conversations where several of our existing pharmaceutical manufacturing customers asked if we could apply our long-standing enzyme engineering expertise to deliver an enzymatic route of RNA synthesis. Since those early conversations, we've made great technical progress, and we've already received enormous interest in our platform from existing customers, CDMOs, and potential tech partners, reinforced by the engagement we saw during the recent TIDES Europe meeting. However, we've also heard from a few skeptics in the analyst and investment communities. Questions have been raised about how much demand for RNAi therapeutics is really coming, whether there's truly a need for an alternative manufacturing method, and whether an enzymatic approach is the right innovation. The purpose of today's event is to tackle those questions head-on. As we've said before, we don't expect the ECO Synthesis platform to own the entire manufacturing landscape, and phosphoramidite chemistry will continue to play a critical role. However, we do staunchly believe that as additional RNAi therapeutics are approved to address large disease indications, a huge gap will emerge between the demand for those medicines and the ability of drug developers and manufacturers to produce commercial scale quantities. Fortunately, you don't just have to take our word for it. We'll kick off today's agenda with presentations from our KOLs, who'll share their perspectives on the topics I've just outlined. Then, our Senior Vice President of Research, Dr. Stefan Lutz, will dive into a technical overview of the ECO Synthesis platform, highlighting the critical differentiators that set our solution apart from other synthesis approaches. Closing out the formal remarks, our Chief Operating Officer, Kevin Norrett, will provide insights into our evolving commercialization strategy and review our upcoming milestones to help you track our progress. From there, we'll head into Q&A, where our KOLs will join us in answering your questions. The hope is that today's event will provide further clarity on the significant market opportunity ahead, and why our ECO Synthesis platform is poised to address a key unmet need. We look forward to a rich discussion, and with that, I'll hand over to Dr. Maraganore. Thank you. Thank you, Stephen. It's really great to be here, and I'm, I'm really thrilled to be engaged with Codexis on this important area of technology development. I won't go through my background because I think Stephen has helped there. But I will just briefly mention that I, I do have a number of external commitments that I'm involved with. So for my disclosures, these are listed here, and as I like to say to people, you can, you know, listen to my words at your own, at your own peril, if you will. But obviously, just want to be transparent about all that. Okay, so let's dive into this important area of research. So I think it's, it's particularly an exciting period for the advancement of genetic medicines today. We've seen gene therapy products that have reached the market. We've seen RNA-based vaccines, basically these save humanity from the perils of a pandemic. We've seen advances in gene editing technologies, which even today will mark an important moment when hopefully the FDA approves the first gene editing product, but this has already been approved by the MHRA. But the area of genetic medicine that I'm particularly excited about, and one that's pertinent to today, is really around the use of silencing oligonucleotides for the advancement of a whole new class of medicines, which is what we did at Alnylam with RNA interference. But to be clear, this also includes approaches such as antisense oligonucleotides, where there are also a good number of approved products as well. In that case, there are about also another six approved antisense oligonucleotide products. So, but of course, in my case, the focus has been on RNA interference, and in fact, the work that I began 20 years ago, over 20 years ago now, when we started Alnylam and got going, was really based on the discovery of this basic mechanism for control of gene expression, which is present in all cells. We reasoned at that time that if we were successful in harnessing this endogenous pathway for control of gene expression with synthetic small interfering RNA molecules, which are the molecules that mediate RNA interference, that we could, in fact, create a whole new class of medicines, which could, you know, ideally rival what is achieved with small molecule drugs or monoclonal antibodies or recombinant proteins, and that was the big vision that we had back in 2002. Thankfully, as I think you'll hear, that vision is well on its way to becoming more of a reality. Now, when we got started, we knew that there would be challenges in making drugs out of small interfering RNA. These are large molecules, around 14,000 daltons molecular weight. They're highly charged. They're prone to being degraded by exonucleases and endonucleases. They can also stimulate unwanted immune responses, and therefore, exhibit tolerability issues if they aren't appropriately, chemically modified. But most importantly, we knew that these molecules, because of their physical chemical properties, would be rather challenging, from a delivery perspective. Namely, the ability to get these molecules from, you know, ex vivo, a vial into a human, parenterally, and then ultimately across the cell membrane in a manner that would allow it to harness the RISC pathway, the RNAi machinery pathway, inside of a cell to achieve its desired pharmacodynamic effect, and so we knew that this would be challenging. Now, thankfully, with quite a bit of effort, two important delivery approaches emerged and ultimately were quite successful. The first is the use of lipid nanoparticles, which was used for the first approval of an RNAi therapeutic medicine called patisiran or ONPATTRO. That's in fact the only RNAi therapeutic that is delivered with a lipid nanoparticle, because a new approach emerged shortly thereafter, using so-called conjugates, chemically modified small interfering RNA molecules with a ligand, small molecule ligand, in this case a triantennary GalNAc moiety, to achieve uptake into a cell in a receptor-mediated uptake mechanism, in this case, with the asialoglycoprotein receptor. This approach became the favorite approach for delivery of oligonucleotides, such as siRNAs, because of the fact that you could use subcutaneous administration with this strategy, but also because the fact, as you'll see momentarily, that you achieve a remarkable durability of pharmacodynamic effect, which really differentiates RNAi-based medicines from essentially all other classes of medicines that are out there at this time. With those important achievements on delivery, it was only a matter of time before we began to bring products to market. As I said, the first product was ONPATTRO, that was approved in 2018, and then there have been four other products approved at Alnylam and even a sixth product approved this year from Novo Nordisk, based on work that came out of Dicerna. But what's really remarkable about this story is that, on an annual basis since 2018, including this year, there's been a new approval of an RNAi therapeutic medicine, that's reached the market. And I expect that to continue, in the years to come on almost an annual basis, with, in the future, more and more, approvals of this category of medicines. And so, in fact, that's illustrated here on this slide. When you look at the history of monoclonal antibody development, which is depicted in the green, we know that in the early 1990s, starting with the approval of ReoPro, that we began to see the advent of monoclonal antibodies as a new modality for drug discovery and development, with now well over 100, nearly 150 monoclonal antibody products that have been approved over the years for a wide range of different indications. I think this is, in fact, very parallel with what I predict to be the case with RNAi-based medicines, with the early approval, first approval in 2018, the beginnings of early approvals that have been happening over the last five, six years. But for the future, and I'll show you a slide on this later, I expect that we will begin to see dozens of these RNAi therapeutic products that reach the market, helping patients around the world in a way that really matches, if not potentially even exceeds in the future, the breadth of potential that we've seen with monoclonal antibodies. Now, I wanted to highlight a few trends that are emerging in the RNAi field, which are relevant to this discussion. First, the transition from rare, more limited high unmet need clinical indications to more prevalent disease opportunities, the transition from liver delivery to extrahepatic delivery, which is important for the growth of this category, but then the final category of the pharmaceutical industry's return to its great interest in RNAi as a class of medicines. Well, let's talk about the transition from rare to prevalent, and this is a slide that we used at Alnylam to depict, in fact, our direction of travel from the early approvals that we engineered in the rare disease settings with drugs like ONPATTRO and givosiran, as well as lumasiran, to products that we believe could make an impact in a prevalent disease setting, which is exemplified by the drug inclisiran or Leqvio, which is now commercialized by Novartis, who acquired The Medicines Company. And the interest in this transition really came out of the large studies that were conducted by The Medicines Company, the ORION phase III clinical studies, that began to read out in 2019 and thereafter. But it was in those studies that they were able to demonstrate that a once every six monthly dosing regimen of inclisiran, which is a small interfering RNA targeting PCSK9, can achieve a well over 55% reduction of LDL cholesterol, again, with biannual dosing. A really remarkable, durability for, reducing LDL cholesterol, targeting PCSK9 with this approach. And very, very importantly, as it relates to the broader application of, of small interfering RNAs in prevalent diseases, was the safety profile that was revealed in this, in this comprehensive multi-thousand patient clinical, program, where the safety profile of inclisiran was essentially indistinguishable from placebo, with the exception of some mild, generally mild and transient injection site reactions, which were led to very few discontinuations in the, in the study. So it really was the combination of the durability of effect, the, effectiveness as well, but most importantly, the safety profile that emerged, that really has enabled the applications of RNAi for these prevalent disease indications. Earlier in the Alnylam pipeline, now in phase II clinical studies, is another example of this as well, namely zilebesiran, which is being developed for the treatment of hypertension. And you can see on the left-hand side that a single dose of zilebesiran, given on day zero, can generate a multi-month-long suppression of angiotensinogen, which is the substrate for angiotensin II, which is the mediator of hypertension. And you can see on the right-hand side that this approach results in a 10 to 20 millimeter mercury systolic reduction of blood pressure, which really is very, very impressive, and then of course, the safety profile as well. So it's these type of data that really have opened up the excitement about RNAi in more prevalent diseases. And as you look across the industry, putting aside the work that Alnylam is doing in hypercholesterolemia and hypertension on the upper left, you can see a larger number of efforts in diseases like hypertriglyceridemia, elevated LPA, NASH or MASH, as well as obesity, where there are ongoing RNAi therapeutic programs in development across the industry, in some cases by large pharma companies, that are really advancing for these prevalent disease opportunities. This is an important trend going forward. Now, the second trend of interest is really the transition from liver delivery to extrahepatic delivery. And we're really seeing an exciting amount of data coming out of both Arrowhead Pharmaceuticals and Alnylam, who together are pioneering the delivery of siRNAs to other tissues. Just this year, Alnylam had beautiful data with an approach using a C16 conjugate, where they presented data in CNS studies. I'll show you those data in just a minute. But also, Arrowhead Pharmaceuticals has generated some data with lung delivery of siRNAs, and over the next year, we all expect to see data in humans from both muscle and adipose delivery of small interfering RNAs in a wide range of different indications, both rare and common disease indications. I can speak to the Alnylam data that were presented earlier this year in patients that received an siRNA targeting amyloid precursor protein for the treatment of early-onset Alzheimer's disease, and you can see the very robust knockdown of amyloid precursor protein alpha or beta in the CSF of humans that received an intrathecal dose, single intrathecal dose of ALN-APP. And this really does speak to the potential now of addressing neurodegenerative diseases with small interfering RNAs using this C16 conjugate-based technology, which will certainly grow the overall opportunity for RNAi-based medicines. Now, the next trend, which I want to speak to briefly, is that pharma has now come back to the RNAi field with a vengeance. This is, for me, rather wonderful to see, because it wasn't that long ago, back in 2011, that Andy Pollack, the famous, science reporter at The New York Times, who's since retired, wrote an article entitled "Drugmakers' Fever for the Power of RNA Interference Has Cooled." And that was based on a period of time in which, in fact, RNA interference was disfavored within the pharmaceutical industry because of the challenges of achieving delivery of that modality. But boy, things have changed, and when you look now at the deal-making that has occurred, both acquisitions, as well as, you know, partnering deals that have been done across the industry, there's, there's basically not a single pharmaceutical company right now that has not reentered or entered for the first time, the RNAi field, in a very, very robust manner. And just over the last five years, there's been $17 billion of deal making that's happened in this field. And one of the reasons these large companies are excited about RNA interference is, in fact, due to the prevalent disease opportunities for this modality, and some of the data I highlighted earlier in this talk. So these are the important trends going forward, and I do think they're relevant to what Codexis is doing, very importantly, because it speaks to the significant need for increases in RNA manufacturing capacity. Not just the increases of capacity, but also the lowering of cost of goods. You know, today's methods have their limitations. What's important here is that when you look at the growing pipeline of oligonucleotide therapies that are in development, there are really hundreds of programs that are currently in development across both biotech and larger pharma companies. Over 100 programs that are in clinical development alone, including many that are in late stages of development. When you forecast the growing need for oligonucleotides, from a manufacturing perspective, just over the next seven to 10 years, you can see that the capacity forecasts grow from 1,000 kg annually, currently in 2023, to over 30 kg, 30,000 kg annually, over the next seven to 10 years, a remarkable growth in the overall requirements. This is an important, an important issue. When I was leading Alnylam back in 2014, we began an effort to build our own manufacturing capacity at Alnylam to migrate away from third-party manufacturing, and built a over $300 million facility in Massachusetts, 200,000 sq ft, to enable drug substance manufacturing. And this is certainly going to be an important part for Alnylam in terms of manufacturing going forward. But we recognized at the time the critical need for new methods of manufacturing. And in fact, my parting words to the Alnylam head of process development as I was leaving Alnylam, a guy by the name of Lubo Nechev, was, "Lubo, the future of RNAi rests in your hands." And I said that to Lubo because of the absolute need for solutions around novel methods, methods of synthesis to really be able to realize the full potential of RNAi as a new class of medicines. And so with that, I'll turn it over to Dr. David Butler, who will take it from here. David? Well, thank you very much, John, and it's great to be able to share this opportunity with you today. It's a privilege to have been invited by Codexis to speak on this topic. In addition to presenting interesting and formidable challenges, I think this area holds immense potential for shaping the future of our entire industry and improving the deal that patients get at the end of the day. So firstly, some disclosures. I'm presenting on behalf of Codexis and have been compensated as such. The content is my own and was developed independently, and I serve as a board director for Aimmune Therapeutics. So I think we'll start with a little bit of history just to provide some context for what follows. Really, it's a rich tapestry that's the history of oligonucleotides or oligos for short, and we find ourselves standing on the shoulders of the giants who came before us, really. Our journey begins in 1949 with Alexander Todd's revolutionary synthesis of ATP and his first oligodimer synthesis in 1955. Bob Letsinger's solid-phase synthesis breakthroughs and Govind Khorana's synthesis of the first gene set the stage for future innovations. The early 1980s ushered in a new era with Kelvin Ogilvie's so-called gene machine, which was the first solid-phase automated synthesizer, and Marv Caruthers' revolutionary phosphoramidite chemistry. Married together, these represented a game-changing advance for oligo synthesis. Since then, there's been huge advances made in the compositional chemistry of oligos that's helped to turn them into durable, efficacious, and safe drugs. And also, there's been huge advances in the synthetic equipment and processes, but it's, you know, it is the case that oligos are still synthesized on automated synthesizers using phosphoramidite chemistry. Along the way, we've seen the unfolding of RNA therapeutic modalities, including ASOs, aptamers, siRNAs, and more recently, single-guide RNAs. And these have given us life-altering medicines. 21 drug approvals since 1998, and 18 of those have come since 2016. And most recently, the green light from MHRA for Casgevy, the gene-editing medicine, which arguably heralds a new dawn for medicine. So as we look back at this history and its milestones, we're reminded that we're crafting the future with threads from this past and that the future of oligo therapeutics looks very bright indeed. So let's take a look at how oligos are manufactured today, and this fundamental approach applies for everything from small scale for research up to large-scale GMP for clinical and commercial development, and it applies for most therapeutic modalities. There are some exceptions, including PMOs and mRNA, that have their own processes. But we start with a solid support, and that's either controlled-pore glass or polystyrene, and that has reactive functional groups on its surface from which the oligo will be grown through formation of chemical bonds. So the support is loaded into a stainless steel column, and the diameter of that ranges anywhere from a few millimeters to around a meter for large-scale manufacturing. And that's then plumbed into a synthesizer that has all of the different synthesis reagents attached, that are then pumped through the synthesis bed in a pre-programmed sequence to assemble the oligo linearly. So a typical cycle to introduce each nucleotide subunit consists of the steps in the figure on the right-hand side. So firstly, deblocking uncovers these reactive functional groups that can then be coupled to an activated phosphoramidite to generate another reactive intermediate called a phosphite triester, that's oxidized or thiolated to make the phosphate or phosphorothioate backbone linkage. Finally, any residual reactive groups are chemically capped to prevent the formation of impurities in future cycles. So repetition of this results in the length of the oligo increasing by one nucleotide for each iteration, and that occurs up to 21x for a typical oligo component of an siRNA duplex, which is actually two oligos that are hybridized, so there's a sense and an antisense strand. And so the total number of steps to make an siRNA duplex can be north of 160. We then transition into the so-called downstream processing steps that include things like cleavage and deprotection, and chromatographic purification, desalting, concentration. And in the case of an siRNA, there's this extra step called annealing that brings the two the sense strand and the antisense strand together, and then that can be lyophilized into a stable powder before QC testing and release. So we can get up to about 50% yield with this process, and 90% purity for a typical si. And yeah, if you think about the number of steps and the complexity, it's really remarkable and speaks to the extraordinary progress that the field has made since the inventions of Ogilvie and Caruthers. The technology has adapted well for rare diseases with smaller volume needs. But you know, about 60% of drugs in current oligo pipelines are now for non-rare disease indications, and so there are significant challenges with meeting future demand. After decades of process improvements in solid-phase synthesis, we're now reaching the point where there's diminishing returns in efficiency, and there's a growing need for innovation in manufacturing technologies of tomorrow. So we can go through some of the pain points, and firstly, the high cost is driven by several factors, including the process mass intensity, or PMI, which is defined as the number of kilos of raw materials that go into manufacturing a kilo of drug. Typically, for an oligo, that's around 4,000, which is really very high indeed. Coming along with all of those raw materials is very expensive waste disposal for hazardous materials. The raw materials, particularly amidites, supports, and resins, are expensive. The synthetic process is complicated, it can require bespoke equipment. Purification can be challenging for longer or modified oligos, particularly, and this can all of these things add to the cost. The extent to which solid phase can be scaled up using columns is limited to about 2 mol or 5 kg of purified API, and that's the limitation there is the height of the synthesis bed in the column, which is constrained really by the physics of the fluid moving over the solid support and the requirement for even flow to get clean reactions. So for a ton of API, currently, we might need as many as 205 kg batches. When we do, when we synthesize lots of small batches like this to make one large amount, that's called scaling out. This paradigm is less preferable compared to scaling up, where you get a fewer number of batches to make the same amount, and under that kind of paradigm, you can reap the rewards of scaling efficiencies. There's a big environmental impact resulting from the high PMI and low atom efficiency, and these other parameters here that we'll discuss in a future slide. Then there are quality concerns, particularly for longer oligos, and you can imagine as the length increases, then it becomes less efficient to generate the target molecule. So you end up with issues like batch-to-batch reproducibility, and it's also harder to get the kind of purity levels that are increasingly expected by regulators. Also, it's not uncommon to hear about total yields of one gram per millimole or less, which for a typical 100-mer single guide RNA, corresponds to less than 5% overall yield. So let's take a look at the CDMO landscape, and as we heard from John, the oligo therapeutics market is experiencing significant growth and, you know, is expected to grow much more in the future. And so this creates a favorable environment for contract development and manufacturing organizations, or CDMOs, and they specialize in providing oligo manufacturing services, and that sector of industry is responding in anticipation of the projected growth, as we can see from the table. This table is intended to be illustrative rather than completely comprehensive in its coverage. But all of the established players at the top have announced significant investments in growth, totaling more than $1 billion since 2021, and there are now at least a dozen emerging players, including Hanjin, where I now work. Even in the context of this dramatic response from CDMOs, it's fair to raise questions about whether we'll have the capacity necessary to meet the increasing market demand, these projections, particularly if there's largely a reliance on scale-limited solid-phase methods. So, responding to this and driven by the growth of their own product pipelines, several prominent biopharma companies are investing in their own internal manufacturing capabilities. CDMOs are keenly aware of the limitations of solid-phase methods and are competing to develop their own improved technologies. And I've called out three in this table. So firstly, liquid phase synthesis, or LPOS, where instead of being grown on a solid support, the oligo is anchored to a molecule that confers favorable solubility in organic solvents. Secondly, stirred-bed reactors, where the oligo is manufactured in a batch reactor, kind of like how a peptide would be manufactured, and the advantage here is that you can scale up. And lastly, ligation, where the oligo is synthesized from multiple shorter fragments, and then joining them together with ligases. So as a case in point, Hongene, you know, we're actively embracing these innovative technologies and also making some excellent progress with our own ligation technology. So it's really important to note that, these advances, hold great promise for, reducing cost of goods and, increasing scalability compared to solid phase. But they're all reliant on the same reagents as solid phase, and, therefore, they suffer from many of the same performance, and environmental drawbacks. I think it's great. You know, wherever possible, we can take, the pulse of the industry, and, we're fortunate that, in the last couple of months, Informa, you know, they, they organized the yearly TIDES conference, which is the biggest oligo conference in the world. They released the results of this very interesting survey, where, you know, people were questioned on the subject of sustainability practices in oligo manufacturing, and responses were received from 110 participants, all involved in development and/or manufacturing of oligo therapeutics. And so there's some selected results shown here. So a majority of respondents, and I think you'd have to assume, by extension, their businesses, are very concerned about waste during oligo manufacturing, and nearly half suggest that they're likely to invest in ACN recycling technologies. And of interest for this audience, 59% are at least familiar with enzymatic synthesis, and 71% believe that solid phase will be superseded by liquid phase or enzymatic technologies within 10 years. So I think this is great. It raises awareness in the field and gets people thinking about the problems. And yeah, hopefully we'll see you know, follow-ups to this survey in the future. So now we're comparing what would be the anticipated performance of a fully optimized enzymatic process versus some of the technologies we spoke of earlier, including solid phase. So this table shows a subjective traffic light weighing of several important performance criteria that would be considered to assess pros and cons of these different manufacturing processes against each other. And these criteria are all important factors in determining COGS for oligo products, and you know, we all need these things to be economically viable, so it's very important. I want to stress, this analysis has caveats. Not, not all the information is available for the, for the different processes, and also there are variants on, on these processes, that, that might cause, the pros and cons to, differ a little bit from, from what they're anticipated to be here. But anyway, let's talk through, some of these things. So a key advantage of solid phase and ligation technologies is that they're fast, whereas a liquid phase process, that generally requires iterative precipitation and isolation steps, that can take a long time. Like I said, there's, you know, there's different types of liquid phase processes, and, and so there might be some nuance here. The modeling for fully enzymatic processes indicates that they should be, they should also be fast, competing with solid phase and ligation. Assuming that enzymes can be engineered with appropriate characteristics, we'd expect to see advantages for a full enzymatic process versus solid phase with respect to product purity and yield, leading to reduced purification costs. Calling out the giants of the field mentioned at the beginning of the presentation, chemical processes are highly, highly adaptable to all kinds of chemical modifications, whereas there could be limitations for enzymatic processes that would require further engineering. Being reliant on the same amidite processes, the chemical processes all generate large volumes of waste, and that's expensive to dispose of. But for liquid phase and ligation, we might expect improvements versus solid phase for those processes when they're fully optimized. Fully enzymatic processes, meanwhile, there's a reliance on water as the solvent, which is less costly to treat and dispose of. Additionally, the raw material building blocks, which are mononucleotides, can theoretically be made using aqueous solutions and biocatalysis as well, enzymes. And that's realistically never going to be the case for phosphoramidites, so that's something that's a forward-looking consideration towards further improvements. The 12 principles of green chemistry were introduced by Paul Anastas, who's kind of the father of green chemistry, and John Warner in 1998. These are important 'cause they guide the design of chemical products and processes that minimize the use and generation of hazardous substances, thereby, you know, mitigating environmental and health impacts associated with chemical manufacturing. They can also make chemical production more cost-effective by reducing waste and energy consumption, benefits everyone. So these principles have been embraced by EPA and factor heavily into corporate ESG strategies, particularly for big pharma, who take them really very seriously. So again, it's a subjective traffic light analysis with similar caveats. And this analysis builds on one from Andrews et al., where they rated solid-phase against these principles using essentially the same approach. And where all we're doing is comparing the other processes as well. So as might be expected for solid phase, liquid phase, and ligation, all relying on the same basic reagents and synthesis cycle, the assessments are really similar across these principles. Where liquid phase and ligation most likely would have a benefit for optimized processes would be in atom efficiency or yield, which as noted would have a knock-on effect in reducing waste. An optimized enzymatic process would be expected to do well, I think, for yield and reduced waste, and may offer clear advantages in with some of these other criteria, including improving energy efficiency, using renewable feedstocks, reduced impact due to chemical derivatization. That's the number of protecting groups or the extent to which those are used during the process. It's a catalytic process, being enzyme-driven, and with it being in water would be a generally more safe process. Okay, let's say you're a CDMO and you're thinking about introducing enzymatic manufacturing into your facility. These are some of the strategic considerations. Firstly, financially, there has to be a clear understanding of investment, CapEx, operational costs, weighed against potential savings. At the end of the day, we're all going to make decisions based on economics. From an engineering perspective, we've got to have the right infrastructure and capabilities to support a process like this. Just for example, batch reactors might be required. Decisions would need to be made around whether those are single-use systems versus, you know, stainless steel reactors. We might need to make decisions about environments, so it might be possible that we could use a controlled, non-classified environment instead of more rigorous controls, and that could help to bring down the costs. Workforce adaptation is essential, so we've got to retrain existing staff or hire new people to handle the new processes. Supply chain management, the focus here has to be on the quality and consistency of the raw materials, and that might necessitate building up a reliable new network of suppliers. Given that the raw materials for the fully enzymatic process are novel at this point in time, and challenging to synthesize, this shouldn't be underestimated. But it is worth pointing out that, you know, the solid-phase synthesis field has faced this with the sphingomyelin material, sphingomyelin over the years, and these challenges have always been overcome. For quality control, irrespective of how you're doing things, the goal remains to ensure the highest standards possible through robust analytics and in-process controls. Now, viewing this from the perspective of a drug sponsor, similarly, there are strategic considerations. So stickiness refers to the extent to which a drug sponsor is kind of stuck with their current process. Solid-phase synthesis is deeply rooted in the industry. It has a proven track record, as we've discussed. People trust it, its platform. Once a particular CMC strategy is set, it can be challenging to justify even small changes within a process, let alone a shift to an entirely new process. So, you know, there has to be demonstrable advantages in terms of cost, efficiency, quality to justify a move. It's also critical to identify a good CDMO partner. You know, we would need them to presumably have a reputation for innovation, and a track record for GMP services and exemplary technical capabilities. Regulatory considerations are important. So when we're moving to an enzymatic process, a regulator is going to see this as a biological process, like they do for messenger RNA, in which case, you'll find yourself at CBER and not CDER, where the majority of oligo drugs end up. So CBER's generally seen as having a more complex regulatory framework, so this is important to navigate. You know, to add to this, many mRNA drug sponsors are asking companies like Hongene to manufacture their raw materials to GMP standards, so that also has to be negotiated. Quality control presents new challenges. Presumably, there'll be new or different impurities compared to chemical methods that will require an update to methods and product specifications, including control for residual enzymes. The stereochemistry of phosphorothioates, the backbone, that's a crucial quality attribute, and this has been demonstrated multiple times to impact the durability, efficacy, and safety profile of oligo drugs. The diastereomeric composition is notoriously challenging to measure, and enzymes may require additional engineering to control for this. Lastly, I'd like to just recap on some of the requirements and also talk a little bit about the future of enzyme technology. For the future, for the oligo industry, the adoption of enzymatic technologies, it hinges on meeting several key requirements. First of all, the COGS, the cost of goods sold, and quality metrics should be on a par with or exceed that of solid phase or competing synthesis methods. We need reliable and stable material inputs to assure the good production of oligos. The technology has to be sufficiently flexible to accommodate a variety of platform chemical modifications, such as those listed here, that you know, these are the essential components of most siRNAs now, and medicinal chemists are very good at inventing new modifications, so there has to be a constant kind of anticipation of those within the industry. The research landscape is rapidly evolving, and we might expect a future that's, that's bright for enzyme enhancements, you know, coming from the convergence of artificial intelligence and directed evolution. The exploration of key siRNA patents is opening that field up to expanded adoption, as John mentioned, and it's fair to say that we can expect in the future a lot of interest in the field with the ongoing advances and discoveries with gene editing. So a shift by industry will be evidenced by market-driven transitions to improve manufacturing technologies. And you know, pharma companies are increasingly tapping into siRNA assets with high-volume potential. And you know, there's clearly a role for optimized enzymatic synthesis to you know, streamline the production of these and similar products. And then there'll also be a focused effort on refining and improving single-guide manufacturing processes to accommodate the potential growth in that field. So in conclusion, enzymatic methods could potentially bring, I think, huge benefits to the oligo industry, theoretically offering a blend of economic efficiency, high-quality output, and a more environmentally friendly alternative compared to existing methods. In the future, where we have this paradigm of large-volume oligonucleotide drugs, it's going to be really interesting to see how all of this pans out and how enzymatic, solid-phase, and the other technologies that we spoke about are going to perform and compete together as the manufacturing technologies of tomorrow. So now I'll hand things back over to Stephen. Thank you. And thanks to both Dr. Butler and Dr. Maraganore for sharing your valuable perspectives. You've just heard from our key opinion leaders about the anticipated demand trajectory for RNAi therapeutics and the very real concerns about the ability of today's manufacturing infrastructure to keep up. They also highlighted that a potential solution in this space needs to have high-volumetric productivity, it needs to address the supply of nucleotide building blocks, and it needs to reduce the massive capital infrastructure investment required. So now I'm going to hand things over to Stefan, our resident technical expert, to review how our ECO Synthesis platform will stack up to those requirements. Stefan, over to you. Thank you, Stephen. Happy to address those points. I'm thrilled to be here today to discuss the exciting technical progress we have made to advance the ECO Synthesis platform. ECO Synthesis technology is Codexis' answer to the challenges of finding an enzymatic route to ribooligo nucleotide synthesis. We've introduced this platform at the TIDES U.S. meeting in May 2023, and we believe it offers an innovative new solution to address the scalability, impurity profiles, and environmental burdens that our KOLs just outlined. Let me tell you, in a bit about how this technology works. At the center of Ecosynthesis is an iterative two-step process, consisting of an extend and deblock step, to build an oligonucleotide sequence one nucleotide at a time. In step one, the process begins with a substrate oligonucleotide in solution. With the help of a highly engineered, template-independent polymerase, we can add or couple a ribonucleoside triphosphate. The polymerization beyond the single addition is prevented by a three-prime blocking group. The efficacy of this addition is measured as the coupling efficiency. Upon completion of the extension step, the polymerase is removed, and we move to step two, the deblocking, which involves an engineered phosphatase that eliminates the blocking group, and it also deactivates the excess of the ribonucleoside triphosphate in the reaction mixture. That results in formation of the N+1 product, which is ready for the next round of extension. Now, as mentioned by Dr. Butler, it is important to emphasize that this process is water-based in its entirety. Complementing the core technology, I want to point out that Ecos ynthesis is also being developed to include reagent supply. This element of the platform offers enzymatic processes for production of blocked ribonucleoside triphosphates, an area where we can leverage our extensive experience in engineering similar molecules for our pharma manufacturing business and for assembly of starter oligonucleotides. In both cases, Ecosynthesis provides an alternative to chemical methods for the synthesis of these critical substrates. We think that Codexis is ideally positioned to successfully deliver on these complex technical, technical challenges that is the ECO Synthesis platform. Let me remind you, that enzymatic oligonucleotide synthesis is not a new idea. Besides the fact that nature has been using these enzymes since the dawn of life, and I might add, quite effectively, I want to reinforce Dr. Butler's statement that, and I'm citing, "We're crafting the future oligonucleotide synthesis with threads from the past." In the 1950s, the early days of oligonucleotide synthesis, scientists actively explored both enzymatic and chemical methods. In a classic example of a technology whose time has not yet come, the enzymatic approaches soon fell behind, in no small part due to the inability to tailor and optimize enzyme performance and manufacturability to the specific application. Today, things have changed. Building on Nobel Prize-winning discoveries, Codexis possesses one of the leading enzyme engineering technologies named CodeEvolver. CodeEvolver technology is a fully integrated design, build, test, learn platform, leveraging the latest and the best of computational design and learning tools, combining that with state-of-the-art molecular biology and high-throughput screening capabilities. Over the two decades, we have successfully deployed CodeEvolver to commercialize over 50 engineered enzymes in adjacent markets. Some of them we are producing in gram quantities, others in metric tons. Codexis is also not new to oligonucleotide synthesis. Two years ago, we successfully engineered a polymerase for enzymatic DNA synthesis, an enzyme that today achieves greater than 99.9% coupling efficiency under process conditions. Our next stop is the grand-scale synthesis of an RNA oligonucleotide, an opportunity for us to demonstrate the preparative scale manufacturing of an oligo composed of modified nucleotide building blocks typically found in an RNAi therapeutic asset, and doing so under process-like conditions. So let me walk you through, in a bit of detail, where we are today. While enzyme engineering and process development are ongoing, we have taken on our way to grand-scale synthesis, our latest polymerase and phosphatase for an oligonucleotide synthesis test drive with three noteworthy takeaways. First, the concept of running Ecos ynthesis with the oligo in solution and the enzyme immobilized works. With it, we can open up new opportunities in regard to process scalability. Second, we can show you today six consecutive ribonucleotide additions using building blocks with different 2'-modifications on the sugar moiety and various nucleic bases to prepare a fully modified ribonucleotide oligonucleotide. Lastly, we have achieved average coupling efficiencies of roughly 92%, close to our initial threshold target of 95%. So what's next for this technology? Current engineering and development efforts focus on establishing the ECO Synthesis platform for modifications found in today's RNAi assets. Specifically, we're looking at 2'-methoxy, 2'-fluoro, and phosphorothioate modifications. Besides scaling up the process, which is where the gram-scale synthesis comes in, we're also driving towards more additions, giving us access to full-length oligonucleotides of 20+ building blocks. Similar synthesis of the second complementary strand followed by a simple heat-cool cycle to anneal the two strands, then produces the final double-stranded RNAi therapeutic asset. Success here is only the beginning. Imagine this to be the original iPhone. It's already a highly impactful innovation, but there are so many great features and capabilities that we can add and improve over time. So, for example, we have an opportunity to steadily drive coupling efficiencies to levels of greater 99%, equivalent to what we have achieved for enzymatic DNA synthesis, with many potential benefits to oligonucleotide quality and yield. Some of the new features that are already in the works include the expansion of the toolbox to enable post-synthetic modifications of oligonucleotides, from simple ligation of multiple oligos into longer sequences to bioconjugation for attaching cellular target moieties. Second-generation or the next generation of RNAi therapeutics, currently in preclinical and early-stage studies, feature additional modified building blocks, such as 2'-methoxyethyl, unlocked and locked nucleotides. Future version of the ECO Synthesis platform will focus on incorporating some of these new building blocks. We believe that the ECO Synthesis platform has potential to unlock exciting new possibilities in RNAi therapeutic manufacturing, and so we're incredibly pleased with the technical progress our team has made. Now, I will pass over to Kevin to share his thoughts for the commercial side. Kevin? Thanks, Stefan. You've just heard about why we're in a good place to meet this challenge from a technical standpoint. Now I'd like to highlight our commercial strategy, how our commercial strategy is evolving and share a few insights from recent customer interactions. We have already started preparing the market for our ECO Synthesis technology through directed education with potential customers. These efforts have helped us identify likely early adopters with the highest unmet need and have also generated insights into the barriers we'll need to overcome. Between TIDES USA in May and TIDES Europe in November, we've seen a meaningful increase in ECO Synthesis engagement and interest from all types of customers. Much of that is due to the massive technical progress we've made over the past six months. As an example, we see clear interest from small and medium-sized contract development manufacturing organizations, or CDMOs, including several that Dr. Butler referenced during his presentation. Many of these groups are interested in either entering the oligonucleotide synthesis market or scaling their existing capabilities. It is also clear that they are focused on finding ways to mitigate the massive infrastructure investment necessary to manage the organic solvent waste and handle the substantial downstream processing and purification associated with traditional phosphoramidite chemistry. The interest demonstrated by these CDMOs has helped us better envision what a longer-term commercial partnership could look like, and we continue to expect that potential technical collaborations and early access customer testing will evolve through 2024. In addition to our customer traction, I want to reiterate a few other key elements of our commercialization strategy. Let's start with market segmentation. While there are multiple RNAi therapeutic modalities, there are a few reasons behind our decision to initially target siRNA with our ECO Synthesis platform. First, as Dr. Maraganore mentioned, while most of the currently approved siRNA therapeutics are targeted towards small, rare disease indications, many of today's pipeline assets are being developed to address widespread diseases like hypertension, Alzheimer's, hyperlipidemia, and diabetes. It's these programs that are anticipated to drive a bulk of the expected increase in RNAi demand over the next five to 10 years. Second, from a technical perspective, the ECO Synthesis platform's initial capabilities are best suited to address many of the synthesis limitations inherent to siRNA. As you heard during Stefan's presentation, there are a common set of modifications in siRNA, and if we get those right, we can apply the technology to other RNAi therapeutic modalities. One critical component of the ECO Synthesis platform is our double-stranded RNA ligase. This enzyme could accelerate our ability to synthesize longer oligos, as it can stitch together short strands of RNA that have been chemically synthesized. For example, we could stitch together multiple short-mers to create a 21-mer. The double-stranded RNA ligase is also positioned to be our early entry strategy into the oligonucleotide synthesis market, and it should address some of the purity and yield challenges associated with phosphoramidite chemistry. Ligation-based approaches are already available on the market, and they continue to grow as a modality because of their immediate cost-saving impact. In addition to enabling customers to manage more complex RNAi molecules, our double-stranded RNA ligase is expected to provide a way to introduce an enzyme to GMP process and familiarize customers with working with Codexis. In many ways, we view the double-stranded RNA ligase as the gateway drug to Ecosynthesis. We will continue to share updates on our product roadmap for other enzymes in the ECO Synthesis platform over the course of 2024. But as a quick summary, our initial ECO Synthesis product offering is expected to consist of enzymes, reagents, and a process designed to enable the production of siRNA. Down the line, we also expect to be able to provide an enzymatic route to manufacture critical reagents, such as the modified nucleotide building blocks. The future product roadmap also includes partnering with technical collaborators to develop a small-scale oligonucleotide synthesizer, aimed to address the discovery and preclinical phases of development, where smaller quantities of RNAi need to be generated. And eventually, there is potential for us to produce oligos ourselves as a service offering. Finally, it is important to note that our overall entry into this space doesn't require a huge commercial footprint, as there is significant overlap with our existing pharma manufacturing customer base. These long-standing relationships open the door to drug developers and innovators, which make up another segment of the market that we think will need the ECO Synthesis platform. Our established history in this legacy business also gives us the credibility to show new drug developers that we can engineer enzymes, effectively scale them up to multiple metric tons of manufactured product, and incorporate them into workflows and processes for downstream drug approvals. Let me wrap up by highlighting our upcoming milestones. We are on track to meet gram scale synthesis before the end of the year and expect an announcement in the coming weeks. This proof point enables us to begin pre-commercial testing with select customers next year, followed by early access commercial licenses of our technology, anticipated in 2025. These phases will allow us to collect valuable feedback and inform any necessary modifications before the planned full commercial launch in 2026. In parallel, we also plan to make our engineered double-stranded RNA ligase widely available for customers in the second half of 2024. As is evident, 2024 is a pivotal year in terms of ECO Synthesis technical and commercial progress, and we look forward to keeping you updated. With that, I'll hand the call back to Stephen. Thanks, Kevin. You know, hopefully today's presentations further validated the manufacturing problem we're solving for and provided some insight into how we're thinking about the key questions on the commercial side. With strong technical momentum and projected cash runway now to fund our planned operations to positive cash flow, we believe Codexis is well positioned to execute on this potentially enormous opportunity. Now, we'd be happy to take your questions, and we're pleased to have both Dr. Maraganore and Dr. Butler joining us for this portion of the presentation as well. Tara? Thank you, Stephen. So at this time, we will be conducting a question and answer session with our speakers. As a reminder, if you'd like to ask a question, please use the Q&A text box at the bottom of the webcast player. Please hold for a brief moment while we poll for questions. So our first question comes from Allison Bratzel from Piper. Please go ahead, Allison. Hey, thank you for hosting this event and for taking the questions. I have one question for Dr. Maraganore and one for Kevin. So first, for Dr. Maraganore, I was struck by some of your commentary on how pharma interest and investment in RNAi has heated up of late. So my question is: do you expect that trend to accelerate? Or maybe, you know, what needs to happen for this to accelerate, and what role does the development of improved manufacturing methods, like enzymatic methods, play in that trend? Or maybe another way of asking this is, you know, have manufacturing limitations been a gating factor to increased investment in this therapeutic modality? And then separately, a question for Kevin. I was struck by the framing of the double-stranded RNA ligases, the gateway drug to Ecos ynthesis. So just hoping you could talk a little bit more about that, you know, early interest in it, and just what kind of milestones we should be looking for in 2024 and thereafter. Thanks. So, Allison, to address the first question, you know, I mean, look, it's, it's wonderful to see the pharmaceutical industry's renewed interest in RNA interference. And as you know, you know, there are multiple programs that are underway in the hands of large pharma, ranging from, you know, companies like Amgen, you know, Novartis, you know, Roche, amongst other large pharma companies. Novo Nordisk has made a big commitment, and many of the programs are focused on large, prevalent disease opportunities based on the, you know, remarkable durability and, and, you know, wonderful safety profile that has been demonstrated for, you know, this modality. And so you do see a significant amount of interest come back. But absolutely, manufacturing is one of the key elements that everybody realizes has to get solved to realize the full potential of the modality. And it was an issue, and it certainly will continue to be an issue for those companies that have come into the space, like Novartis, when they acquired The Medicines Company with inclisiran. You know, they are quite keen to think about how they can increase the scale of manufacturing and also how can they use enzymatic-based approaches and non-chemical-based approaches to be able to do that. And that's just dealing with the use of these agents in the developed world. I mean, when you start thinking about other more, you know, broader applications globally for these medicines, there's going to be a very significant need for these type of methodologies to enable the expansion of the opportunity. So yeah, manufacturing is very much top of mind as these companies are coming into the space, for sure. So on your second question, jumping in around the double-stranded RNA ligase, we do see this as incredibly important. As you heard Dr. Butler mention, ligation methods are already in the marketplace. There are some wild-type double-stranded RNA ligases being used to enhance the current phosphoramidite chemistry methods. What we would be bringing to market would be an engineered version, of which we've been working on for some time, and quite frankly have also already had customized arrangements with several of these key players ongoing. So it's a combination of both our customized programs reaching completed evolution and getting into the hands of those customers, but also launching our own engineered version in the second half of this year. So I think we've made great progress, actually, believe it or not, since TIDES as well here, as they've already put in place several MTAs, and we're starting to transition material to a few select customers. And we hope those translate into commercial sales in the second half of 2024, and that's our plan leading into 2025. Excellent. Thank you. Thanks for the questions, Allison. Our next question comes from Chad Wiatrowski from TD Cowen. Please go ahead, Chad. Hey, guys. Thanks for this event. This is Chad on for Steven Mah. To start, I guess, what's the current state of the modified bases for RNA stability, and will future next-gen bases be able to be used in an enzymatic process? So, John Maraganore, would you be willing to take the current state? And then I'd like- Yeah. To have a bit of Stefan to talk about how we're tweaking the enzyme. Yeah. I mean, there are literally a handful of chemical modifications that are currently being used in the pipeline of either existing products that are on the market or ones that are in development. These include 2'-fluoro modifications, 2'-O-methyl modifications. The use of some novel nucleotides, like GNA, is one that will need to be considered. Obviously, phosphorothioate backbone modifications are used selectively in a couple of places, typically. And there is an increasing interest in the use of vinylphosphonates, you know, at least one in the 5'-end of these siRNAs. So those are the types of modifications that are used and will have to be considered as part of the enzymatic methods. Yeah, I certainly think that, as I pointed out in my presentation, our current focus of ECO Synthesis platform development is on, on the very residues that, Dr. Maraganore just pointed out, the methoxyfluoro and phosphorothioate. But also, as I've mentioned, there is full intentions to generate future versions of Ecos ynthesis that starts incorporating, emerging needs for new modified building blocks in these therapeutic assets. So this is going to be, you know, future versions, 2.0, 3.0. So, Chad, you just saw our strategic advisory board in action there, which is, you know, part of the role of that group, is the sort of reconnaissance on where the field is going. And I'd like you to sort of note Stefan's comment about this being the iPhone 1.0, and part of the challenge for us is continued innovation to include these new modifications and ever-improving efficiency. And, you know, we think that Codexis is uniquely equipped to address that challenge, which is why we're quite so excited. Right. That's helpful. And maybe another one for you, Dr. Maraganore. Could I just add one thing to that? Yeah. Which is the other trend I'm seeing is that companies are looking at where the manufacturing synthesis is and using that as or the enzymatic synthesis of state-of-the-art is, and using that as a way to think about what modifications they're willing to include. Because these are, you know, upon design, these molecules can be chosen to have some of these modifications and different flavors of modification. And so increasingly, companies are beginning to think, "Okay, how do I integrate the manufacturability considerations, particularly with an enzymatic method, much earlier in my design and selection of my development candidate before I make the commitment?" Which makes complete sense. Yep, that's helpful. And I guess, I guess just to touch on your slide on delivery technologies, where are we today in lipid nanoparticle delivery innovation and the use of modified nucleic acids that can improve the stability of RNAi therapeutics and thus the potency? Like, how much better can that get, and can these efficiency gains offset the need for high amounts of RNA therapeutics, like, for example, Alnylam's second-generation AMVUTTRA, which uses much less RNA than the 1st- gen on ONPATTRO? Yeah. Well, I mean, first of all, I'd say this, you know, the lipid nanoparticle approach for synthetic oligonucleotides is, I think, going to be pretty short-lived because of the trend of the industry to go toward conjugate-based approaches. And so in the case of Alnylam's pipeline, there's only one product that uses a lipid nanoparticle, and that's ONPATTRO, relative to the other approaches. And while there have been improvements in potency that have occurred, like AMVUTTRA, which uses a quarterly dosing regimen, relatively low dose, those improvements of potency are being offset by demands of volume and so, you know, the volume demands are really driving, you know, the greater needs for these type of technologies. For example, the zilebesiran program, which is, which is, you know, in hypertension, a very large prevalent disease setting, will probably need a Q6 monthly dosing regimen of somewhere between 300 mg and 600 mg per dose, which of course, is gonna be a big challenge. And therefore, the need for novel synthetic methods like the Codexis approach. So the bottom line is, these are better medicines. That improving the availability will improve the usage, increase the usage, and get to more of the people that actually need them. So we actually see that as a good thing. And by the way, it makes a cost-effective manufacturing method even more important if they're gonna have even more widespread use. Yeah, absolutely agree. Thanks again for the questions, guys, and congrats on putting this all together. Thank you. Thanks for the questions, Chad. Our next question comes from Matthew Hewitt from Craig-Hallum. Please go ahead, Matthew. Good morning, and thank you for hosting this event. Maybe first off, Dr. Butler, you were talking about some of the considerations for CDMOs moving towards the enzymatic approach. And kind of looking at that list, I'm just curious, how big of a hurdle are those, you know, items actually? You know, you think about the cost to manufacture, the solid dose manufacturing, process plants and whatnot. It seems to me that it's a relatively low bar, but maybe just talk through how big of a hurdle it actually is for CDMOs to adopt the enzymatic approach. Well, I think that with the right sort of mindset and the right kind of approach to innovation, that yeah, some of these barriers kinda come down a bit. So I think that, you know, there are CDMO partners that would be really good to work with, that have kind of a reputation for innovation, a reputation for providing, you know, that would be, you know, ready to shift with the technology. And, you know, those would be easy to identify and the ones that you would work with preferentially. Got it. Kevin, do you wanna talk about how our current conversations map to what Dr. Butler just said? For sure. I mean, I think that segmentation that Dr. Butler is talking about is incredibly important in terms of our ability to execute upon some early commercial licenses, and I think those that have kind of emerged already from our conversations at EU TIDES have already helped us with that segmentation. I mean, we must have had over 30 meetings at that, at that conference itself, based upon the technical progress we made, and, and we're starting to get to the brass tacks of actually, you know, how do we put in place an agreement to get them the product in their hands for testing and further enhancement? Got it. Thank you. And then maybe a separate question: so if you're successful, or maybe we say when you're successful, will it be about the future therapies adopting the enzymatic approach, or is there an opportunity to go back to the 100+ that are in the clinic, the drugs that have already been approved, to convert to the enzymatic approach and kind of re-go through the process and launch from there? Thank you. So that's an incredibly important question, and one that we're working on right now. Obviously, the clearest path is to adopt new molecules at the beginning of development and take them through pre-clinical testing and all the rest of it, but one of the places that we're looking at is actually the analytical bridge for existing molecules. And, you know, sometimes this is gonna be about the ability of a company to move from a small indication to a big indication, so there's a real unmet need. And, you know, analytics is key, and one of the beautiful things about the gram scale milestone coming up around the end of this year is that that will be at a scale that will really allow us to start developing the analytical framework for real. Okay? And so this is something that is absolutely front of mind, because if we can show a path to switching from one route to the other, it will happen. It's already happened in the small molecule space, where, you know, one of our biggest enzymes was originally a chemical process that switched to enzymatic biocatalysis. So it's happened before, and we believe we can make it happen again. That's great. Thank you very much. Thank you for the questions, Matthew. This concludes the verbal portion of our Q&A session. I'll now turn it over to John Mulally of LifeSci Advisors to read the remainder of the questions from the webcast. Great, thanks, Tara. Yeah, we do have a number of submitted questions, and I think we have time to get through a few of these. I'll start with the first question: If scaling the manufacture of these products is such a big problem, why aren't we hearing more about it? That's a great question, and, John, would you like to take some of that, and then. Yeah Kevin and David? Yeah. Yeah. I mean, look, you know, I'm not surprised the investment community isn't necessarily hearing about this, 'cause it's sort of the stuff that goes on, you know, behind the scenes. But I can tell you at the industry level, it is a very, very active area of interest and need to get it solved. And, you know, I mean, I don't think the investment community necessarily hears about, you know, recombinant DNA manufacturing plants that often, and all these type of details, because that's in the engineering part of the business that we're all engaged in. and so that's why I don't think you've heard very much about it, but it is a absolutely significant and real important thing that needs to get worked on and solved for the future of this category, no doubt. So, David Butler, you're in the trenches on this. Is this a live conversation? Yeah, we have conversations regularly, both internally, about, you know, how we're going to be innovating to meet this anticipated change in the market. And we also have the conversations externally with our drug sponsor partners. So yeah, it's definitely a very important topic of conversation for CDMOs like Hongene. Great, thank you for that. Thank you for those responses. I'll read the next question: How important are ESG considerations to you, and how much value do you place on the potential of the ECO Synthesis platform to reduce environmental burden? So one of the things that we're proudest of at Codexis is our heritage in green chemistry, and really we've applied that to pharma manufacturing before, and that has been a central consideration in the genesis of the ECO Synthesis platform. But again, I'd like to hand that over to our KOL experts to give a sort of outside-in view on the importance of ESG. John? I mean. Maybe I'll start, and David, you'll have more to touch on. But, you know, when we built the over $300 million facility in Norton, Massachusetts, for drug substance manufacturing at Alnylam, you know, the number one consideration was the handling of all the acetonitrile that was needed for the manufacture of siRNAs, and we had to build a very significant capability for that. But it also weighed into a lot of the cost considerations, because the disposal of the waste, you know, linked to that use of acetonitrile is a major component of cost in the manufacturing. So it is a big factor, not only from an environmental standpoint, but also from an economic standpoint. And David, you probably have some more facts you can share. Absolutely, John. Thanks. Yeah, so, ESG considerations, environmental sustainability, for us is extremely important. We're incorporating these principles into the design of our own facilities. And, you know, we have goals to be net zero by a certain date. And we're incorporating recycling technologies for acetonitrile. And so, you know, these are very important factors for us. They're extremely important for many of our partners, too, particularly on the large pharma side, where ESG is an integral part of their corporate strategy, and they have goals to meet around this. And, you know, as good partners, we need to help them achieve those goals. So here's a fun fact just to illustrate that making a kilo of siRNA through phosphoramidite chemistry uses about 1,000 L of acetonitrile. Burning off 1,000 L of acetonitrile is about 2.5 tons of carbon. So, you know, these are very big numbers, and things where we think we have a huge opportunity to impact, and it's front of mind, the ESG story. Great, thank you. We will now take the final question, as we're running out of time. The question is this: What do you need to see to believe that ECO Synthesis platform is real? So we are super excited about unveiling the gram-scale synthesis and then continued progress at the TIDES meetings next year, but I'm going to give this the final shot with John Maraganore and David Butler. What do they want to see to say this is for real? I mean, from a innovator/manufacturer perspective, it is to see, you know, the direct success of using the approach. The, if it's for an existing product, the analytical comparability that gets achieved, if not improved upon, with the enzymatic method, and then ultimately the regulatory handling of all that, which I think should be very straightforward. But it's really just the reduction into practice that will be, you know, the most important thing to see, for sure. Right. Just, uh- Uh- Sorry. I'll just add to that, that, you know, that those are really, really important. I would love to see those, those aspects, front and center. And then, you know, cost modeling, would be important, too. You know, as soon as we can get something around that, just to demonstrate that we have, something that's economically viable. Right. Thank you to everyone that submitted a question. Sorry we weren't able to get to them all, but we are running out of time. This concludes the written question portion of our program, and I'll now turn it over to Stephen for closing remarks. Well, thank you everyone again for joining us, and we hope you found today's presentations on the potential opportunity for our ECO Synthesis platform informative. We're very grateful to our KOLs for their participation in this event and for Dr. Maraganore's ongoing guidance as a member of our strategic advisory board. We're excited to continue our work to bring the ECO Synthesis technology to market, and we look forward to sharing additional updates in the coming months, including when we connect with many of you live during the upcoming JP Morgan Healthcare Conference. So with that, I'll hand back to Tara. Thank you, Stephen. This concludes today's presentation and Q&A session. You may now disconnect.