Okay, let's go ahead and get started. My name's Ally Bratzel. I'm a biotech analyst here at Piper. Thanks for joining us at our healthcare conference, and it's my pleasure to introduce Codexis. So joining us today for the fireside, we have Chairman, President, and CEO Stephen Dilly. So, this is meant to be an informal format, so if anyone in the audience has a question, just go ahead, raise your hand, we'll get to your questions. So first, just to get going, maybe, you know, Stephen, a lot of things have changed since you came to Codexis, you know, strategic refocusing, meaningful extension of the cash runway, tangible progress on ECO Synthesis. So just, you know, high level, walk us through some of that and kind of what is the value proposition for Codexis now and your, your vision for the company.
Thanks, Ally. It's great to be here. So Codexis has a long history in building an expertise around enzyme engineering and applying enzymes to manufacture of drug product. And my job when I came into the CEO role just over two years ago now was to work out what the sort of most valuable go-forward strategy was. And, you know, part of that was looking at the base business, which is making biocatalysts for small molecule API production, and seeing that as a very attractive but finite proposition in terms of, you know, just how much value you can capture from that sector of the market. But then saying, so where else is there an unmet need that we can address?
And really looking at all the things we could do with the emergence of oligonucleotides as therapeutics, that was quite compelling, and particularly RNA, where to make current siRNA drugs requires a significant investment in infrastructure and chemical handling and all that kind of stuff. And we realized that with work we could probably build an enzymatic solution to that and be a much more sort of significant player in the value creation. And so it was really, you know, like that sort of Michelangelo thing where you take the slab of marble and you get rid of everything that doesn't fit on the statue. That's what we've been doing with Codexis and a lot of sort of offloading of non-core assets and technologies.
So we can focus the business now in what I call manufacturing 1.0, which is the small molecules, then 2.0, which is individual enzymes in oligonucleotide manufacturing like our ligase, and then 3.0, where we actually produce the therapeutic itself.
Excellent. That was a good kind of intro to the company. Maybe kind of staying high level for those newer to the story, just kind of walk us through the ECO Synthesis platform itself, you know, how you address unmet needs and how your platform enables scalable manufacturing for siRNA therapeutics.
Sure. So in order to talk about how we provide the solution, I have to express the problem a little bit, which is, currently the marketed siRNA drugs are manufactured chemically using a technique called phosphoramidite chemistry. This is a system based in organic solvents such as acetonitrile and toluene. It is very reagent intense. It takes about 7,000 kilos of input to make one kilo of output. It has an enormous impact on the environment economically and chemically. There are significant downstream disposal costs. And to give you an order of magnitude, Agilent, one of the very big CDMOs in the space, spent more than $700 million in building a facility in Colorado that can make about a metric ton of siRNA a year.
We believe that by the end of this decade, the worldwide supply will need to be more like 20 metric tons per year of siRNA if you look at the enormous pipeline of drugs coming. That seems like a real stretch in terms of just availability of a platform. What we've built is an enzyme-based system in water, so it's aqueous-based, where we use a very exquisitely engineered polymerase enzyme to sequentially add the building blocks to make the RNA medicines. We've got to the stage now where we've already made the existing drugs that are on the market at small scale. A few weeks ago, we actually showed our ability to manufacture the leading drug in Inclisiran in many different ways to show the flexibility of the platform. Maybe we'll talk about that a bit more later.
But what the ECO Synthesis platform is, is an ability to use enzyme technology to make siRNA in a, we believe, cheaper, better, faster way.
Excellent. So maybe kind of going back to your Michelangelo analogy, you know, I think you kind of outlined what gave you the confidence to strategically pivot, and go all in on ECO Synthesis. I guess, you know, sitting here today, a few years since that pivot, you know, how has that view changed, if at all? I mean, it seems like it's been strengthened, but kind of based on your experience with, you know, customers in the field, just how are you thinking about that?
If I'm honest, the decision to make the strategic pivot was visceral rather than logical, and I'm damn glad we did. And it really came from a conversation with one of my favorite scientists at Codexis where we were talking about siRNA, and I said, "Do you think we can do this?" And he said, "Maybe, but I'm sure no one else can." And that was what really sort of made the hairs on the back of my neck stand up, was to say, "Okay, that's a competitive advantage. We can pull it off." And so there were six months of skunk works to actually get the enzyme, which didn't work at all on RNA to start with, working on RNA, and then starting to work on the modified building blocks.
About 18 months ago, we got to a stage where it started to look technically feasible. You know, the sort of first coming out was at a meeting that's called TIDES, which stands for, you know, the Nucleotides Meeting, which is a real sort of geek-out fest of people getting together who are usually doing chemistry. The first time we rolled this out in sort of spring of 2023, we'd done five sequential steps with an enzyme, and we were completely out of left field, and people thought, "Well, that's lovely, but it's never gonna be ready for prime time," and so on, and so you know, but yeah. We came back and we'd done a full-length strand by the sort of fall of last year.
And then we started, you know, to make real progress through this year. We're just a few weeks from the TIDES Europe meeting, where it was a completely different flavor in that enzymatic synthesis had gone from being a footnote or a sidebar to everyone was talking about it, and so there is a general recognition that there's this gap in the supply chain for RNA medicines and that, you know, enzymes can be the solution, and how do we get there, and so the conversation is now about how do we get there and scaling rather than whether this is a good idea, so we see a complete, you know, validating sea change, and, you know, it's sometimes better to be lucky than good. I think we've been a bit of both here.
Mm-hmm. Excellent. And maybe one last, you know, a little bit higher level question is, I guess, help us understand how you're thinking about, you know, the platform, the revenue potential for ECO Synthesis. You know, describe the value proposition for an innovator or CDMO customer and kind of what you're working towards.
Okay. We have to step back and put this in context of the overall business. We've done some really hard work around the heritage business to turn it back to being a growing, profitable baseline. And so, you know, that's probably a top line of $40 million right now in terms of product revenue. And then that grows, and it increasingly margins improve. And so we have a cash flow positive business, that section of the business, which throws off oxygen to really fund eco. Now, we have a stepping stone between the pharma manufacturing business and the fully enzymatic platform, which is the ligase business. And we already have several commercial customers signed up where we are supplying them with a double-stranded RNA ligase that can stitch together short strands of RNA to make the full drug.
You know, the difference there is we move from a few thousand dollars a kilo for an API manufacturing enzyme to a few thousand dollars a gram for the double-stranded RNA ligase. So we've gone way up the value chain. Those two together build us a growing, you know, cash flow positive business, with existing products, with existing customers within the next two years. Now, then you layer ECO on top of that, right? And we're looking at different economic structures with different players. If we're talking with a big innovator company, what we're interested in is being adopted across their pipeline where we can get, you know, licensing fees for access to the technology.
We can get milestone payments at various stages of progression, and then we can supply them with the wherewithal in terms of raw materials and enzymes and other technology to make their drugs across the pipeline. With a CDMO, it's about enabling them to service multiple customers, so again, it's access to the technology and access to the materials to make stuff. When we're talking with earlier phase companies, the vision is broader than that. It's actually to become a direct supplier of siRNA, and we've started that with our ECO Innovation Lab.
Our sort of long-term goal is to get into cahoots with a lot of early phase companies making their siRNA, supplying them directly, and not just the white powder, but also the analytical framework, the regulatory advice, all of that kind of stuff, so we can be a true development partner and we can get, yeah, upfronts and milestones and licensing fees and then royalties on the back end. So different business models customized to the different partners.
Excellent. I know you mentioned TIDES, Europe, and, you know, at that meeting, you had significant progress on a number of fronts. And I think you've described that meeting as being kind of a pivotal moment for Codexis. Just, you know, discuss the key takeaways and just why this was a pivotal moment for the platform.
First of all, people had actually heard of Codexis, which is great. You know, the presentations were attended, you know, very well. We did several different really cool things. One of them was a presentation showing the fully enzymatic synthesis of inclisiran, the Novartis drug that's the biggest siRNA asset at the moment. We showed not just that we could make a strand, that we could make both strands, and then we could make the targeting moiety. We actually moved from making oligonucleotide sequences to making a drug. That was cool. We showed that we could do it in many different ways depending on the particular sort of circumstances at the time. One of them was making it in chunks enzymatically, synthesizing them and then stitching them together. It was making the chunks chemically and stitching them together.
And then it was making some chemical, some enzymatic, stitching them together. And the sort of punchline, the mic drop moment was analytically, they all look the same. So this was something that people had a big aha moment saying, "Oh, so there's a stepwise progression from my chemical synthesis of my molecule to introducing a ligation enzyme to make my chemistry better, to introducing some things enzymatically, to eventually going fully enzymatic." That was important. And then we had a co-presentation with Bachem, one of the big CDMOs in the space, where we showed our ligases outperforming the ligase that they usually use. And when I say outperforming, I mean better conversion efficiency, better volumetric efficiency, better flexibility in terms of reaction conditions. So people could actually say, "Okay, this part of the platform is ready for prime time.
I can adopt it right now." So it was, the comment we got back from a number of big innovator companies was, "We thought this was three or four years in the future. It's actually now. It's ready." And so we've had a lot of inbound since that meeting.
Excellent. And yeah, that kind of gets into my next question as, you know, you kind of described the shifting, you know, TIDES in terms of CDMO innovator and innovator views on ligation and things like that. So just maybe dig into that a bit, and kind of help us understand what it means for your business.
Right. So it's interesting. You discover things as you move along on the journey. We thought that we were totally innovating when we were starting to look at ligases and optimizing ligases, only to realize that a lot of the big companies already had used a ligation step. They'd just been using available enzymes. And so what we thought we were inventing the mousetrap, actually what we were doing was making the mousetrap better, which is actually easier because people are more willing to adopt. And so our first commercial customer was actually a large pharma company that had been using a ligation step, looked at our ligase, and it actually worked better. So they it was worth them swapping out their enzyme for our enzyme as they moved from Phase II to Phase III.
Now, with that first order to enable them to do that was single-digit millions. That will be followed by double-digit millions and so on. So for an individual enzyme in our pharma manufacturing business, our heritage business, we sort of aspire to $5 million a year in revenues. With a ligation step in a decent-sized RNA drug, it can be an order of magnitude bigger in terms of, you know, we're not surprised if it can be $20 or 30 million in there. As we move towards the direct supply of siRNA, then you're talking about $1 million a kilo as a base price for GMP-grade material. And so if we're supplying, you know, 100 kilos, yeah, it's a very significant revenue stream. So we see this as really the sort of breakout potential for Codexis.
Excellent. I think you mentioned, you know, the innovation lab, and which I think is slated to be ready to go soon. I guess, walk us through why that rollout is important, for your ligation customers.
Yeah. So it's important for our ligation customers, but it's also important for our full ECO Synthesis customers. So what the innovation lab is, it's bringing together technologies that have been done in different parts of our facility into one place with controlled access and controlled workflows so that we can move from laboratory material to GLP, which will enable partners to actually use this material for their tox studies and sort of preclinical evaluation. The capacity of the lab is probably about 100-gram scale, and that allows us to supply multiple customers over the course of a year. We have two conversations ongoing right now that we believe will be, you know, consummated within the next few weeks that will fill the capacity of the Eco Lab in 2025.
And, you know, that's with it coming on stream in general and working full throttle through it throughout the year. So that's, that's really exciting. And what it allows us to do is optimize process so we can demonstrate, you know, the ligation step, what that'll do to the efficiency of the process, etc. But then we can also develop the, the optimized enzymatic process for these, for these partners so that can be adopted going forward.
Excellent. I think, you know, one of the steps from, you know, moving from GLP manufacturing to GMP, involves a partnership with CDMO, I think, which I think is in the works. So just, you know, talk about what that could look like and, and kind of what is your ultimate goal on the manufacturing front?
Right. So it's great to be able to show people their drug made in the laboratory enzymatically and without all the sort of infrastructure that you need. They say, "That's cool." Then you show them GLP drug, and it's actually useful, but only if you can show them a path to GMP manufacturing, right? Now, building a GMP plant takes time and takes scale, infrastructure, and all the rest of it. The demand is such that we need to move faster than we could by building de novo ourselves. So therefore, we are in, you know, very deep, very advanced conversations with what we're calling scaling partners.
And that will be companies with existing facilities where we can put our technology into their footprint and run it either for them or they will run it for us, but partnered in there going forward so we can get access to kilos and tens of kilos of GMP-grade material in the sort of 2026, 2027 timeframe so that we can now bring people into the ECO Lab, build their ideal process for them, scale it through GMP, tech transfer to the GMP partner, scale it for clinical development, and then we're off to the races. You asked about our aspiration. Our aspiration is also in parallel with that to build our own GMP facility.
Whether by build, I mean build, or we walk into a distressed facility that we can get for cents on the dollar, you know, think cell and gene therapy, wide open spaces, and, you know, put our equipment in there. It could be either of those. We're in sort of intense assessment of that right now. One of the beauties of our technology is it is so damn simple to implement once you've built the enzymes. Because when we do a sort of show and tell in the ECO Lab or whatever, people say, "Is that it?" It's because enzymes are doing all the work.
It's essentially, yeah, a couple of tanks and a column that does this as opposed to what people are used to seeing is, you know, explosion-proof containers for acetonitrile and all the downstream disposal stuff and all the rest of it. So really, the beauty of this is the enzymes doing the work.
Excellent. So I know we're getting kind of close on time here, so I want to just ask about, you know, near-term and long-term timelines. So I guess, you know, walk us through your timelines, your anticipated news flow for ECO Synthesis in 2025 and then in 2026 with your full roadmap rollout. And then, you know, longer-term broadening out the scope of this question, you know, thinking about the end of the decade, you know, how are you thinking about the platform expanding to adjacent markets, and just what's the longer-term vision?
What's it look like? Well, you know, one of the funny things is, you know, I've been running biotech companies for quite a while, and people keep asking me about what's our big binary event readout. Well, the good news and the bad news is we don't have one, right? This is about execution and scaling and, and, and moving forward, exciting things that are going to happen. Obviously, the launch of the ECO Lab very early in the new year, then there's the partnerships with big innovator companies. There's signing up the scaling partner. There's all that kind of stuff so that, you know, by this time next year, there will be a very clear line of sight on, you know, who we're working with, what we're making, how we're getting it to GMP, all of those sort of i's dotted and t's crossed.
but also multiple customers signed up for our ligation platform, not just the existing ones, but ones that are currently looking at our optimization process. Because one of the things we can do is build a ligase that is uniquely suitable to their molecule and all that kind of stuff. So it really is that execution all on the background of delivery of continued growth in the background business. So, yeah, you can see the sort of increasing robustness of the organization, and then we start to scale from there. And then in the long-term view, we come on stream as a GMP manufacturer of siRNA servicing early-phase customers so we can build those royalties in the long run.
And then adjacent technologies, you know. This technology is applicable across ASOs, looking at some of the new constructs in terms of the microRNA and the hairpins. But you know, we have to pick our battles, and we chose, you know, siRNA is the place to start, but there are many adjacencies for polymerases.
Excellent. So maybe time for one last question. Just on your, on your cash position, you know, I think in the midst of this kind of strategic pivot, you've shown pretty remarkable financial discipline. Can you just, you know, talk about your current position, your guidance for cash flow positivity, and then kind of the assumptions that you're factoring into your, your guidance?
Yeah. We finished the last quarter with about $90 million in cash. We have said that that funds us, with some cushion to getting to cash flow positivity, late in 2026. Now, some of that is dictated by, you know, the growth of the pharma manufacturing business that we have. And that projection is made based on existing customers, existing product, and, you know, anticipated future orders, plus layering on the continued success and moving forward with the ligase. So pretty happy about all of that. And then there comes to, you know, how hard do we spend to really build the trajectory, the rapid growth of the ECO business? And so we are, you know, leveraging partners like, for instance, the GMP scaling partner, at the moment while we prove everything.
But I think there will become a tipping point when, you know, we need to scale and move and move rapidly. So the beautiful thing is we have optionality. The company was rebuilt during the nuclear winter, you know, after the COVID sort of sugar rush went away. That's really good. That is something to guard preciously that we have that real discipline. And so I'm not saying we're not going to spend to accelerate that trajectory, but we're going to be super careful about doing it. And we're always going to be in control of our own destiny. So that's us.
Excellent. Well, and that's probably a good place to end. So, yeah, thanks so much for being here and walking us through the stories.
Thanks, Ally.