All right. Morning, everyone. Thanks for joining us here at the SVB Securities Global Biopharma Conference. My name is Tom Smith. I'm one of the senior biotech analysts here at SVB and excited to welcome our next presenting company, Axcella. From the company, very happy to be joined by CEO Bill Hinshaw. Bill, thanks for joining us. Of course, Tom. It's Tom. It's great to be with you. Of course. Just one quick housekeeping note here for investors joining us via the webcast. Feel free to submit any questions for Bill into the webcast portal, or you can email them to me directly at thomas.smith@svbsecurities.com. With that, Bill, let me hand the mic over to you to run through the presentation, and we'll come back for some Q&A at the end. Great. Well first, Thomas, thank you for hosting me today, and it's great to be here at the SVB Leerink Conference, and I thank all your attendees for their attention. It happens to be a really auspicious day for the company to be presenting with y'all and to announce to you that last night we were able to communicate that the FDA has cleared our phase 2b/3 trial for our Long COVID fatigue program, our lead program at Axcella, and I'm really excited to talk to you about that today and give you the additional details. Let's start, of course, with the fact that, you know, I will be making forward-looking statements through the course of this presentation, and you can see our safe harbor statements both on our website as well as the SEC filings. Let me step back from the long COVID fatigue program just to describe the company and how we got here and why we are the leader in this field. Axcella Therapeutics is a Flagship Pioneering founded company, and your audience will know them, of course, as the founders of Moderna, along with a number of other companies. At the core of each of those companies is a big transformational what if question. Case of Moderna, that was, what if you could use messenger RNA to create vaccines and drug products? In our case, it was, what if you could restore health and homeostasis through putting together combinations of products to address complex diseases specifically, and to do that through using endogenous molecules? In fact, we can, and we have now in 8 straight studies demonstrated the power of this science. We have a platform that has allowed us to rapidly produce pre-phase two ready assets that also provide a significant advantage in terms of not only are they very fast and efficient, but they're highly informative, which allows us to de-risk our next steps in development. Just last fall, we presented compelling data for our lead asset, AXA1125, in both long COVID fatigue, which I'll take you through in detail, as well as NASH. We focused our organization in December on the long COVID opportunity because of the unmet medical need, which is enormous, the speed in which we can seek to address it, as well as the fact that we are the leading program in that area and an opportunity to return to our shareholders, the return we're looking for. At a very high level, Long COVID fatigue is a large growing market with no current therapies available. We have clearance from both the FDA and the MHRA on a phase 2b/3 trial design that will be highly efficient and be in a position to have a modest spend in order to realize the registration data that we're looking for there in the near term. AXA1125 is by far the most advanced program in this field. There are no late-stage competitors. There is a clear blockbuster potential opportunity, and there are very few assets that are phase three new molecular entity that could launch as soon as 25 and be a blockbuster in the near term. We are tremendously excited by the opportunity and potential. Let me step back to the science and really what this is founded on. We're working on endogenous metabolic modulators or EMMs as we call them, amino acids and their derivatives, which are very bioactive agents and molecules that we have really unlocked. How do you put them together in combinations? A lot of progress has been made with single drug targets and looking either at a single pathway or a single binding site and being able to impact that. However, that does not adequately address the needs of complex diseases where multiple dysregulations are ongoing at a time. That's where our ability to do combination by design and put together compositions of these agents, which are powerful master regulators, signaling agents, as well as substrate that have a series of important impacts on the body and allow you to be healthy and address dysregulation. That's really the secret and the distinct approach that Axcella is taking. That's powered by a platform that is truly a design platform, bringing together the power of systems biology and machine learning to design candidates in a highly efficient fashion. First, we identify the biologies on the left, and through combinations of natural language processing, machine learning, and molecular networks, we identify what are the right targets that we can go after. We move into ranking and selecting them through both primary human cell systems and proprietary tools. We select which composition we're putting together in which ratios through a combination of tools on the systems biology side. We get into the dosing directly into people with the disease. This allows us to very rapidly understand the clinical impact, the biological impact, and of course, the advantage that we have across all these agents is they are designed to be multi-targeted, work with the body system be safe and well-tolerated, and in fact, an easy oral dosing approach. This is the platform that has led to three important programs. As I mentioned, last fall, we were able to demonstrate this at scale in multiple diseases where we delivered impact on the long COVID fatigue program, I'll take you through in detail in a minute, as well as NASH, a very large, complex disease where we had three studies in a row demonstrating impact. In fact, the interim analysis we shared last September showed market-leading levels of liver stiffness improvement, as well as continued improvements in liver fat and metabolism and inflammation. Of course, we believe we have a very good safety and tolerability profile since these are natural substances that your body is used to working with. That's been demonstrated across multiple programs. Let me take you into long COVID at this point in time, and I'm going to walk you through on this summary slide, the key points that I think are critical for everybody to bear in mind. Because of course, the pandemic has been a massive impact on people, society, and health, and we're all tired, literally, of this and looking to move forward into a new setting, which is frankly, that it will be endemic. That is not a good outcome. That is the real outcome that this will continue to be with us. As such, AXA1125 indeed represents what can be a potentially transformational near-term commercial opportunity where we can play the leading role in a public health crisis. Let's start on the upper left. We know that Long COVID has now already affected more than 100 million people worldwide, and that is impacting up to 23 million Americans. This is because there is no standard of care, and regardless of vaccine status, severity of infection, or variant, Long COVID, and specifically Long COVID fatigue, continues to pass through. This is because there is a common disease pathogenesis of post-infections, okay, whether it is Epstein-Barr, chronic fatigue syndrome, ME, and we happen to have this affecting a large percentage of patients in the case of COVID. That impact is massive on an individual level. These are athletes who are being dropped off at their front door. These are physicians who can no longer practice, these are parents who feel crippled by their ability to take care of their children. That translates into a massive societal impact. The Brookings Institution has already reviewed and estimated that up to 4 million Americans are out of work and 1 million Americans are disabling. It's this type of data that led Time to indicate that this is potentially the greatest mass disabling event in human history. Fatigue, which is what we're seeking to address, is present in the majority of subjects, unfortunately. We showed strong preclinical and clinical rationale and worked with the experts back in early 2022 to initiate a trial with the University of Oxford, world experts in long COVID fatigue and long COVID and mitochondrial function. We showed compelling data I'll walk you through in the next few slides. This is clearly a blockbuster need and opportunity. We have the opportunity here as well for category leadership. There's very limited competition. There's high inbound interest and need from physicians, governments, and patient groups, of course. We have a long time horizon to realize value here with intellectual property out into the end of 2037. With the phase 2b/3 trial, which I will share with you, we have a highly efficient path to a potential registration. We have a significant safety database already in hand, and we're already advanced on key things like CMC. It will take a moderate investment to take this next step forward and generate registration data. Let me share with you the results of our previous trial. This is a phase two trial, again, conducted with the University of Oxford, looking at AXA1125 compared to a matched placebo. We dosed for 28 days, These patients had to have COVID for longer than 12 weeks post- long COVID rather, for 12 weeks post-infection. They had to have a moderate to severe level of fatigue and no explanation for the fatigue other than the infection. In fact, these patients had on average been in this condition for more than 500 days. We dosed them for 28 days, and we measured mitochondrial, inflammatory, and other functions because we understand the disease pathogenesis to be endothelial dysfunction, inflammation, and mitochondrial bioenergetics. We had biomarkers oriented to those measurements. We also had functional measures. Overall, of course, we looked at safety and tolerability. I will walk you through three very powerful slides here as to the results that got ourselves and the medical community very excited. The first is a waterfall chart that shows the improvement in level of fatigue through the CFQ-11, a FDA-validated tool in the field of chronic fatigue syndrome that is also going to be our primary endpoint in our next trial. What you can immediately see here is that the orange group, which of course is the treated AXA1125 group, has a significant impact and a large cohort effect. This is not one subject. This is almost all of them had an important impact and change in their level of fatigue where the placebo group did not. When we look at that across a traditional statistical analysis, what you see is whether it's total fatigue, physical fatigue, mental fatigue, that we see a highly statistically significant improvement, that we see a change in the level of fatigue that's indicated by the orange horizontal bar, and that the confidence intervals on these are very tight, and that's again because of the power of the impact. This is something that we are very pleased with and is a traditional way of looking at the data. The slide I'm about to show you is what really compels the physicians who treat these patients as well as the patients. That's something called a shift table, which measures the change in level of fatigue. Let's take a look at that. On the left-hand side, you will see the placebo. Almost no change in either physical or mental. Believe me, patients would love to feel better in this case, but they're not in a position to do so because of the biology. What you see is on the right-hand side, in both physical and mental, a profound change, including the fact that 70% of patients had an improvement in the level of fatigue, and 13% of them normalized. That's part of the beauty of the CFQ-11. It measures not how are you feeling versus seven days ago, but how are you feeling versus your normal state. To do this in 28 days of dosing was a profoundly impactful motivation for the physicians and the patients. In quick summary, we showed these highly statistical, significant, and clinically relevant impacts on fatigue. We also showed that a functional measure like six-minute walk was correlated with outcomes and improvements only on AXA1125. How they feel and how they function. We saw a correlation in important biomarkers, whether it's the PCr measurement or blood lactate, as well as supporting our approach. Of course, it was very safe and well-tolerated with no patients discontinuing. This outcome led us to move quickly to the regulatory interactions, both with the U.K. authority, the MHRA, as well as the FDA. I'm very pleased that earlier this year, the U.K. cleared our CTA and supported us moving forward to a single registration trial, aligning on the primary endpoint, key secondary endpoints, the dosing and duration of the trial. That we announced in January of this year. The FDA, we just again announced last night, cleared that same trial design, which allows us to move forward with a phase 2b/3 program, which again, we anticipate will enroll very rapidly. Let me share with you the design of that study. What you have here is a 1-to-1 randomization of AXA1125 versus the placebo. We will be dosing, in this case, for three months, looking at as the primary endpoint, the CFQ-11, the PROMIS tools as key secondary endpoints for how patients function, as well as actigraphy and return-to-work measures. One of the things that's critical about this population is these are not just the elderly or the high at risk. These are 20-year-olds, these are 30-year-olds, these are highly productive members of society. In fact, the average age in our study was 43 years old. These key measures will be looked at, combined with, again, carrying forward the population that we studied previously. Higher probability of confidence there in terms of patients who have had long COVID for greater than 12 weeks and have moderate to severe fatigue by the CFQ-11, which is an exceptionally straightforward as well as validated tool. This allows us to have a rapid opportunity to enroll. In fact, this morning, Dr. Jason Maley, who runs the Beth Israel Deaconess Long COVID Survivorship Program, said he anticipated this being a very easy to enroll study, and he is clear about the demands for needs here because these patients have no options, and these centers have six-month waits or longer. Roughly 300 subjects is our anticipated approach, and we are looking at moving forward and executing this trial upon support and resources and collaboration. Very exciting moment for ourselves and the potential to help long COVID patients. I'll wrap up with a couple of last slides because this need, as I described from the Time article, is keen. We just saw The Atlantic put out another article on this piece. That attention is very clear to the government, medical, and patient communities. In fact, there is a major program occurring next week sponsored by BIO Solve M.E. that is going to be one of a series of programs addressing this issue. You have key speakers like Senator Kaine, Rear Admiral Levine, as well as key leaders across the government and medical community. Dr. Margaret Koziel, our Chief Medical Officer, will be presenting our data as well. Let me summarize the opportunity in this way as a transformational commercial opportunity. You have a de-risked set of data that has now moved from an unclarity or a lack of certainty about the regulatory path to a clear regulatory path based on the data that we've generated. We have an opportunity. We believe we're one of a handful of companies and products that are at phase three ready that could be launched as early as 25 and have blockbuster status as early as 27. That's out of more than 300 phase three programs in the industry. We have a compelling product profile where it is safe, well-tolerated, oral, and multi-targeted, which is critical to address this devastating disease. That's just in the aspects of where we stand with Long COVID fatigue. We believe we have understood a critical disease pathogenesis across more opportunities as well. In summary, Axcella Health is incredibly pleased and proud of the work that we've done with eight straight programs showing impact on biology that has rapidly produced three phase two programs across important diseases. With long COVID fatigue, we have an opportunity to help address this large, growing, and unrelenting marketplace with no current therapies. We're very pleased to be positioned to move forward with the phase 2b/3 on the next steps of this program. Tom, thank you for your team and for the opportunity to present this morning. Great. Thanks, Bill. Yeah, I appreciate the walkthrough and congrats on the important IND clearance you announced last night. It's great to see the regulatory alignment across both FDA and EMA. Yeah, obviously this is an area of high unmet need. Certainly very topical, as you alluded to with the media coverage. You know, I think this is a disease state that's really top of mind for a lot of folks. Good to see you, your development work there, trying to trying to address it. A couple questions. I guess, maybe on the enrollment and the study design here. You know, can you just speak to your anticipated heterogeneity in the patient population? Like, how much variability did you end up seeing on some of the qualitative, efficacy metrics? I appreciate that, comments and the question. I'll go back to the fundamental biology here to address that because we saw a consistent response across the cohort, right? That's what we saw with AXA1125, whereas we did not see those changes in the placebo group. We believe that's fundamental because, again, this is a situation where, like in other infections, but very prominent obviously in COVID, what happens is the virus hijacks the cellular machinery to make more virus. That's its obvious goal. Fortunately, for a good portion of us, we recover once we've had the infection. There are others, based on their underlying biology, either mitochondrial or metabolically, that they're unable to recover. What ends up happening is now the virus has shifted to what's called a glycolytic energy state, which is not favorable for us as people, and that creates inflammation and endothelial dysfunction. The cells are now in a survival mode. Now the bioenergetic piece cannot function properly. What AXA1125 is able to do is address all of those in an integrated way. That's why we believe we saw the 70% of the subjects in just 1 month of dosing see a clinically relevant improvement in their fatigue. This is why folks like Dr. Maley said, "We don't see this in our clinics." These folks, once they pass 12 weeks, they're pretty much stuck, right? That is something where they are being left behind right now by the medical community and the lack of treatment. We don't believe there's a wide heterogeneity in terms of this particular aspect. You can assess have they been infected and do they have a moderate to severe level of fatigue? Very simply, no elaborate blood test, no costly monitoring, you combine that with the profile of the product. This is an exceptionally easy to execute, trial and clinical execution as well for the physicians. Okay. Yep, got it. Appreciate those comments. Just, I guess also in terms of study design... Mm-hmm. Walk us through, I guess, how you've powered the study here. What kind of treatment effect are you anticipating? Yes. We showed the results in our previous study with, you know, 41 subjects. Because we had such profoundly statistically significant and consistent across the cohort to your question. We have powered this study quite robustly. Those are the words of the regulatory authority. We have also incorporated an analysis to adjust it seamlessly if we believe we should resize the study. All right. We have an early opportunity to understand the impact we've had and a seamless calibration opportunity specifically on a change in the CFQ-11 as the primary endpoint. We have consistent measures across the functional measures in the PROMIS 8-C, that is an FDA-developed tool for function, as well as biomarkers that are going to help inform us can we identify patients not only in the 12-week status, but patients maybe earlier who would be prone to sustained Long COVID fatigue that hopefully with our profile we could help address earlier. We're very excited about the, I'll say, the efficiency of this study and the amount of information we're gathering. You can see across the top there that we'll be looking at these PROs quality of life physical measures both at day 1, then you're looking at day 28, day 56, day 84, and then a follow-up. Again, we're anticipating high interest based on the physician response to this need and the lack of other options. Okay. Okay. Yeah, then in terms of the interim analysis, Bill, where it seems like you have some optionality to come in and expand the trial size if needed, is that going to be based exclusively on what's being seen on the primary fatigue endpoint? Or are there other considerations? You know, if you see a strong signal on fatigue, but let's say one of the other kind of functional endpoints, you know, you could have a rationale for maybe expanding the study and trying to tease out the treatment effect across one or the other functional endpoints. Is that, I guess, just an idea of how holistically the efficacy data will be evaluated as part of the interim? It'll largely be focused on the primary, but we will be looking and understanding with the DSMB, you know, what is the overall approach or signal. You know, this is one where we could also, Thomas, have an early win, right? Based on the previous trial, again, the regulatory authorities have been clear that we're powering this well to identify the impact that we're looking for. We want to gather significant information because this is a strategy and an approach to rapidly bring forward this innovation to patients who have no other options. We do believe there are other expansion opportunities both within long COVID as well as other diseases, these disease states that some of that information will inform us on. Okay. Got it. That makes sense. Yeah, I guess, just as you characterized an opportunity for an early win, I mean, You've framed it as kind of an interim analysis for futility. Is there also built into the stat analysis plan an opportunity for superiority at the interim? We'll finalize that with the statistical analysis plan, as you always do with the agency. That's part of something we'll be looking at to your powering question. Again, we believe we have unlocked a critical biology here that should have a profound effect across a large number of the patients. If we're able to demonstrate that, we'll consider whether or not we're in a position to move rapidly forward with that. This is, as usual, Tom, you've covered us for a while now, so you know that we're very thoughtful about our trial design and our optionality, and we've considered that in this important disease. Understood. Okay. another consideration here, I guess, in the overall study size. typically, you know, we think of there being a minimum number of patients that would need to be exposed to a therapeutic for a certain duration of time. just kind of thinking through the intended length of this study, I guess, how are you thinking about generating kind of the longer term follow-up data? Has FDA or MHRA, are they aligned in terms of how much longer term exposure data you would need for AXA1125? Yeah. Obviously that's part of the review discussion we've been having with both agencies. I'll bring your audience back to the fact that AXA1125 has been studied already in more than 200 subjects in the NASH program, including up to 48 weeks of dosing. We have a very significant safety database of actually delivered product of course, this trial will contribute to that. We also know that these are amino acids and they're derivatives. From that standpoint, they are very safe and well-tolerated, and that is a well-established regulatory paradigm as well. From that standpoint, we have a lot of confidence and the, I'll say the tolerability profile, safety tolerability has been consistently demonstrated. This trial, to your point, is three months of dosing, and we believe that that will be adequate to address a number of the patients and hopefully quite a few of them in addressing their fatigue and returning them to normal. There are ways that we can test, do some patients need longer therapy? That's part of what we'll be discussing with, you know, going forward, both with potential, the medical community, potential collaborators, and our opportunity to expand the needs and opportunities of this particular program. Okay. Yeah, that's interesting. There must be consideration to adding some sort of open label extension portion to this. Is that fair? There are 3-4 well-established strategies you can take to address and answer that question. Again, because of the fundamental nature of the biology that goes across the variants, that goes across, you know, the status of the severity of the illness, we believe that in many cases we'll be able to reset that biology with those patients. There are good ways to study that and that we'll finalize in the next steps. Understood. Okay, great. Just last question. I know we're coming up against time, but just I guess current thoughts around whether you intend to take this forward entirely yourself or you're exploring partnership opportunities. I guess just remind us on kind of cash balance and resources, how far you kind of have in terms of runway? Yeah. Let's start on that front because, you know, the organization, we focused the team on Long COVID late last fall, right? In terms of this because of the capital dynamics of the market and the company where we have cash runway well into the Q2 of this year now. That was to achieve these key milestones and give us the best opportunity to move this program forward. We remain very active in discussions with the usual parties that you would expect, but also additional ones because this is such a large medical need, because of the impact on society. It's not just the traditional life sciences organizations that are looking at this, but the governments, hence my comments about this forum that's going to be occurring next week. Left unaddressed, this will have a massive impact on our workforce, on our economics, and is something that needs to be facilitated and supported at a high level. We're working on a number of different types of agreements to take this forward. With these key regulatory milestones, again, this moves from a question of, okay, Long COVID fatigue is we understand the science now, we understand how important it is, and now we have the regulatory path as well. It moves from that level of unknowns to that level of traditional late-stage drug development. We can define now the study, the time, the cost, and the probability based on all the great work the team has done and the results we showed with the University of Oxford. We're going to work very hard with the various parties and remain strategic about whether that's collaboration and/or funding, to move this forward. Got it. Okay. Yeah, that makes a lot of sense to me. All right, Bill. Well, unfortunately, we're up against time, but appreciate you joining us this morning and congrats on the progress and the important news last night. Thank you so much, Thomas, thanks to your audience for their interest. We're excited. Indeed, a big milestone day for ourselves and hopefully for Long COVID fatigue patients. Thank you. Thanks, Bill.