Evelo Biosciences, Inc.

Good morning and welcome to Avello Biosciences conference call to discuss the first quarter 2021 financial results and business highlights. At this time, all participants are in a listen-only mode. Following the formal remarks, we will open up the call for your questions. Please be advised that this call is being recorded at the company's request. At this time, I'd like to send the call over to Jessica Cotrone of Avello.

Please proceed. Thank you. This morning we issued a press release that outlines the topics we plan to discuss today. This release is available at www.avelobio.com under the Investors tab. Today on our call we have Simba Gill, Chief Executive Officer, Mark Bodmer, President of R&D and Chief Scientific Officer, and Jonathan Zung, Chief Development Officer. Before we begin, I would like to remind everyone that statements made during this conference call that do not relate to matters of historical fact including statements about our objectives and anticipated clinical milestones, the impact of our product candidates, and the timing and results of our clinical studies should be considered forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Such forward-looking statements are intended to be subject to the safe harbor protection provided by the Reform Act. Actual results could differ materially from those indicated by the forward-looking statements due to the impact of many factors. Participants are directed to the risk factors set forth in Avello's quarterly report on Form 10-Q for the three months ended March 31, 2021, and the company's other filings with the Securities and Exchange Commission. Any forward-looking statements made today speak only to Avello's operations as of today. Avello disclaims any duty to provide updates to its forward-looking statements even if subsequent events cause the company's views to change. It is now my pleasure to pass the call over to Simba.

Thank you, Jessica. Good morning, everyone, and thanks for joining. 2021 is a pivotal year for us, and we've begun the year with continued strong execution. Together with our partners, we have successfully progressed our research and clinical plans despite the COVID-19 pandemic. And because of this, we remain on track to deliver multiple clinical readouts across psoriasis, atopic dermatitis, and COVID-19 over the next few months. We also continue to advance our extracellular vesicle product candidates in oncology and inflammatory disease. Mark's team in research and development continue to explore, enhance, and extend the applications of syntax-based medicines, and he will give you an overall view of our drug platform in a moment. We have expanded Avello's leadership, appointing Lucas Scarbo as chief financial officer. Lucas starts with us on June 1st. and Julie McHugh to a board of directors effective immediately. Both Luca and Julie have deep and successful track records in building global organizations and commercializing blockbuster products across a wide array of indications. We also announced a strategic collaboration with Abdul Latif Jamil Health to develop and commercialize EDP 1815 in the Middle East, Turkey, and Africa. The collaboration combines Abella's leadership in biotech innovation and Abdul Latif Jamil's regional presence, reputation, and expertise with the goal of accelerating the delivery of effective, affordable medicines to people in these high-growth markets. As we look forward, we continue to make strong progress in executing on our clinical strategy and plans, and Jonathan will tell you more about this later in the call. With that, I will pass the call over to Martin.

Thank you, Simba. Over the last 18 months, a series of clinical and preclinical results have advanced our understanding of the small intestinal axis, syntax. Building Avella's platform and portfolio started five years ago with a vision and strategy which has remained constant. We proposed a way to make a new type of medicines that are both innovative and affordable and that are convenient to take orally and are safe and well tolerated This profile is quite different to other innovative medicines. The science enabling this is a novel way to control inflammation from within the gut with gut-restricted drugs that have effects throughout the body. The key to understanding our medicines is to look at the gut and the profound control exerted by the gut's connections throughout the body. The question was how to make effective medicines to take advantage of this biology. We realized that single microbes could be selected from the gut that behave like conventional drugs with desirable therapeutic effects. We can now also select extracellular vesicles for the same purpose. In preclinical studies, product candidates have properties and a profile that is differentiated from current types of drugs, hence the claim that they have transformational potential to benefit the health and lives of so many people. Three paradigms were challenged. to make this new type of medicine. Firstly, immunology, that there is a control system for systemic immunity centered in the gut. This is not widely appreciated or understood. Second, pharmacology, that this control system can be targeted to make medicines that act at a distance from within the gut without entering the body. Thirdly, the microbiome, that there is an alternative way to think about making medicines based on the microbiome by selecting elements of the microbiota which can have direct pharmacological effects and work in non-live, non-colonizing forms. The ultimate expression of this are the discoveries about the pharmacology of extracellular vesicles. These are three big claims to make, which are all supported by data that you've seen emerging piece by piece, initially preclinical and now clinical. Let's recap the clinical picture of EDP1815. Five studies have shown anti-inflammatory effects with EDP1815, two cohorts of people with psoriasis, a cohort with atopic dermatitis, two groups of human volunteers in an experimental inflammation model. Each of these alone was a small study. Collectively, they show a consistency of effect, proof that a non-live single strain of bacteria can act at a distance from within the gut control systemic inflammation. The three paradigms in immunology, pharmacology, and the microbiome have been effectively challenged. The range of clinical information that's been studied, TH1, TH2, and TH17 pathways, supports the Goldilocks effect, so-called broad resolution of inflammation without overt immunosuppression. And around 300 patients have taken EDP-1815 for between 4 and 16 weeks in several diseases and including hospitalized patients with COVID-19, and EDP-1815 continues to be well tolerated. EDP-1815 is a unique asset in the pharma world. It has an increasing probability of success to become a major medicine. A year ago, it seemed a possible outcome. The data now suggests that it's a likely one. Two more things are worth reflecting on. First, a reminder of the extensive range of preclinical data. EDP-1815 has been compared with the best standard of care drugs in mouse models of all three major forms of inflammation where it's been shown to have clinical activity, Th1, Th2, and Th17. In every case, EDP-1815 and other emerging drug candidates in our pipeline are comparable to, for instance, tofacitinib, fingolimod, and dexamethasone. These are amongst the most potent small molecule anti-inflammatories, all of which are effective but dose-limited by toxicity, which does not appear to be an issue for EDP-1815. It's hard to see any of these classes of drugs being used routinely across the full spectrum of inflammatory disease severity. EDP-1815 and EDP-1867 also compare favorably to mouse equivalents of anti-IL-17 and anti-IL-4 biologics. Again, it's hard to see these in routine use in very large numbers of patients, given their costs. and route of administration. These are remarkable, broad, and consistent effects of EDP-1815, one drug that potentially can match all of these comparators with safety, convenience, and affordability. Finally, new data has been generated about how our syntax drugs work, the mechanisms by which a gut-restricted medicine can have systemic effects. We've identified the biological exchange mechanism, the contact point where immune cells in the gut, which see our drugs, transfer information to immune cells in the periphery, which have the therapeutic effect. This exchange takes place in the lymph nodes of the gut, which are the place where the gut and peripheral immunity meet. The ability of immune cells to traffic through those lymph nodes that link the gut to the rest of the body can be blocked by administering antibodies to receptors that are required for the cellular trafficking. When this is done in combination with EDP1815, then EDP1815 does not exert its effects in the periphery. This inhibition has also been shown for EDP1867, the second anti-inflammatory microbe that has just started in the clinic, and for EDP2939, the anti-inflammatory EV. It's a general property of anti-inflammatory syntax medicines. This is a formal proof of mechanism which explains this new pharmacology. It's the linchpin to understanding that there's a defined system and cellular basis for this newly discovered biology. This has all come a long way quickly, improving what initially seemed an unreasonable idea. Simba and I have early history together from the mid-1980s in some of the very first therapeutic antibody projects. Conventional wisdom was that antibodies could not possibly be drugs. They wouldn't work, they wouldn't be tolerated, they couldn't be made at scale. We know how that turned out. We've leant on that experience to build the Avalo platform for EDP 1815 and all of the other candidate products in our pipeline for inflammation and oncology. Continuing research investment in formulation and extracellular vesicles will allow us to maximize their effects in patients. continuing investment in manufacturing at scale and low cost of goods will enable us to make these new medicines widely available and affordable. Now, over to Jonathan.

Thank you, Mark, and good morning, everyone. As Simba shared, we'll have readouts from several clinical studies in the second half of this year. We remain on track to report top-line data for the full cohort of study participants in our Phase II dose-ranging trial in psoriasis in the third quarter. As a reminder, this is a 16-week trial evaluating three doses of EDP-1815 in capsules versus placebo in approximately 225 patients with mild to moderate psoriasis. The primary endpoint is the mean percentage change in PASI score at 16 weeks. Secondary endpoints include a number of physician and patient reported outcomes across different measures of clinical efficacy. Our Phase 1b trial evaluating tablet and capsule dosage forms using the higher concentration of EVP1815 drug substance is underway in three cohorts of patients, two with capsules and one with tablets. The purpose of these three cohorts is to select the most appropriate dosage form, either capsule or tablet, for our Phase 3 programs. Initial results from these three cohorts are anticipated in the third quarter, along with data from the Phase II psoriasis study. Together, this information will position us to go forward into Phase III trials with an optimized dose and dosage form of EDP-1815. Moving on to EDP-1815 and atopic dermatitis, we're planning to initiate the Phase II atopic dermatitis trial in the third quarter of this year. This will be a double-blind, placebo-controlled trial in participants with mild, moderate, and severe atopic dermatitis. The trial will be conducted in North America and Europe. Our Phase 1b trial of EDP1867, evaluating safety and tolerability in healthy volunteers and patients with moderate atopic dermatitis is ongoing and progressing according to schedule. Dosing in the healthy volunteers is underway. and we will begin dosing of participants with moderate atopic dermatitis later this quarter. The moderate atopic dermatitis cohort will be dosed daily for 56 days with a 14-day follow-up. We will report results from this study in the fourth quarter. Just a reminder that EDP-1867 is from a different genus to EDP-1815 and has been rendered non-live by gamma irradiation. EDP-1867 has demonstrated robust anti-inflammatory activity in preclinical models of Th2 biology. By testing it in patients with atopic dermatitis, we will learn about its potential in treating Th2-mediated diseases. Our two COVID studies are ongoing. The first study, TACTIC-E, is a randomized parallel arm, open-label, adaptive platform, Phase II-III trial, of potential disease-modifying therapies in patients with COVID-19-related diseases. It is sponsored by Cambridge University Hospitals in the UK, with joint funding and drug supply by Avello and AstraZeneca. The planned review of interim data after the first 90 subjects enrolled, including 30 subjects treated with EDP-1815, was conducted by the Independent Data Monitoring Committee in accordance with the protocol. no safety issues for EDP 1815 were identified. The trial has therefore proceeded with continued recruitment. The next review of safety and efficacy data will be after approximately 125 subjects have been enrolled into the EDP 1815 arm. The primary outcome measure is the incidence of any one of death, invasive mechanical ventilation, ECMO, cardiovascular organ support, or renal failure. We've recently opened additional sites in Mexico, Brazil, and India where hospitalizations continue to increase in order to increase enrollment. The second COVID study is being conducted at Rutgers Robert Wood Johnson University Hospital. This study is evaluating EDP-1815 in adult patients newly hospitalized and on oxygen due to the COVID-19 infections. Patients are equally randomized to receive EDP 1815 plus standard of care or placebo plus standard of care for 14 days. The primary outcome is change from baseline to the lowest ratio of peripheral blood oxygen saturation to fraction of inspired oxygen measured up to day 14. Secondary outcome measures include overall survival, WHO COVID ordinal scale score, duration of hospital stay, duration of oxygen therapy, and time to clinical improvement. While we continue to accrue patients in both trials during the quarter, due to the increase in vaccination rates and the lower number of patients hospitalized with COVID-19, we expect both trials will take longer than originally planned. Because we do not know when we will be able to report data from these trials, we will no longer provide guidance on timing for data readouts for either trial. Now, I'll hand it back to Simba for closing remarks.

Thank you, Jonathan. We are at an exciting inflection point for Avello and have a catalyst-rich few months ahead of us with multiple clinical readouts as we head towards later stage development. I'd like to conclude by thanking the team at Avello and our partners whose passion and commitment makes all of this possible. With that, I will now open the call for questions.

Thank you. As a reminder, to ask a question, you will need to press star one on your telephone. To withdraw your question, press the pound key. Please stand by while we compile the candidate roster. And our first question comes from Roger Song with Jefferies. Your line is now open.

Great. Thanks. Can you guys hear me?

Yeah, loud and clear, Roger.

Awesome. Yeah, thanks. Thanks for taking the questions. maybe the first question is related to 1815 phase 2 atopic dermatitis understanding your planning to initiate a trial in third quarter and just curious what are the steps to prepare the initiation and specifically what are the expected endpoints potentially different from the current approved drug in the mild to moderate patient population, which we know are mostly topical.

Thanks, Roger. I appreciate the questions, Roger. So let me say a few words, and I'll let Jonathan expand on the end point. So in terms of steps, as you know, we brought Jonathan on board as our Chief Development Officer. It feels like a lifetime ago, but it feels like yesterday as well. And Jonathan's just been a fantastic addition to the leadership team. And under Jonathan's leadership, we've really built out clinical development capabilities together with our CRO partners. So we're very well prepared already in terms of core blocking and tackling late to the phase two in terms of site identification, et cetera. So all of the fundamental operational things are very much in hand. Obviously, the other key thing is drug supply and everything around tech ops and manufacturing. Chun Zhang heads up tech ops for us is a magician and is constantly able to deliver what we need. And again, we're very much in a great position there. So I think we're just moving forward on plan and should be in a great position to start in that context. Your second question in terms of what are the endpoints and what are we looking for? I'll let Jonathan talk to some of the technical points there, but just to frame the unmet need and the market situation, as you suggested, Roger, atopic dermatitis essentially for moderate and mild patients has no meaningful oral safe drugs. And so patients are limited to using topicals. You've heard us talk before, Roger, about the fact that whilst topicals have a role and we expect always will have a role in treating patients with moderate and milder forms of dermatological disease, there's a huge desire on the part of patients and clinicians to have oral therapy. As you know, Roger, you see the benefit of oral therapies on the psoriasis side in moderate disease where Tesla's just rocketed to a multi-billion dollar product just because it's intuitively obvious patients want an oral tablet or capsule versus having to lather creams onto their bodies every day. So it's a wide open space. The Last meaningful topical to get approved was Crisabrol, Eucrisa. And we certainly expect to have a very competitive product versus Eucrisa or Crisabrol or indeed any of the other topicals. But the point is that we'll be the key oral, safe, effective, and affordable medicine in the atopic dermatitis space. So we're very excited about that, Roger, and really see a very clear path for us having the key defining oral product in the whole atopic dermatitis space. I'll let Jonathan pick up on the technical points about the endpoints.

Sure. Thanks, Simba. And, Roger, in terms of the endpoints, we're looking at the conventional endpoints. We'll be looking at change in EASI, change in IGA. We'll look at IGA and BSA. And then, in addition, we'll be measuring a slew of patient and physician reported outcomes, including POEM, DLQI, score at itch, things of that nature. So we'll be able to you know, fully understand 1815.

Okay, great. Thanks for all the comments. Okay, and maybe just my another question is for your you have two EV product candidates, 2339 and 1908. Knowing you will start potentially start a clinical next year, So just curious, what are the steps into the IMD filing? And given these are EV product versus the single stream, live on and replicating product, what are the key differences versus current Python product?

Yeah. So let me answer your specific questions in a moment, Roger. If you just bear with me. I'm very happy you've raised our EV, our extracellular vesicle program. So I just want to recap that aspect of what we're doing because it's something we're incredibly excited about. So just to re-summarize, I know you understand this, Roger, but I suspect others on the call may not. So EVs are naturally produced microbial extracellular vesicles, which we have discovered can be delivered orally to drive very potent responses in oncology at a level that goes far beyond what we and others in academia and even other companies have seen in terms of oral delivery in oncology. And given that, we're taking forward our first EVs. We absolutely are moving forward towards the clinic. Again, I'll come back to the specific actions and things that need to happen in order to allow that in a moment, Roger. But our anticipation is that we have a real potential to have, again, the key foundational orally delivered immune-activating agent in the oncology world. And as you know, Roger, there's three core pillars to the school of modern IO therapy. Checkpoints have done a great job removing the breaks. That's largely solved. Obviously, there's a range of new products, including Tridelvi, which are doing important things in terms of increasing exposure of neoantigen and antigen to the immune system. But the piece we haven't solved as a broad field is how do we activate the immune system in the most optimal way? People use the analogy of cars. So you can take the brake off the car, but the car's still not going to go anywhere if you don't have fuel in the car and you don't hit the accelerator. And so that's really the key missing piece in our view in immuno-oncology. How do we make sure the immune system is optimally activated? And the preclinical data that we presented at CITSE in November is quite remarkable. We're seeing results preclinically in relevant in vivo models where we're activating systemic immunity at a level which is as strong as the best products that people have seen historically. But those other products are delivered intratumorally and or systemically, and they... typically come with significant side effects, tolerability issues. The results are in line with the type of thing that people became very excited about with sting agonists, for example, a few years ago. So the reasons why EVs are more potent, Mark may perhaps touch on later, but fundamentally, because they're so small, they're about one thousandth the size of a microbe, they can penetrate through the mucous layer to get to the surface of the small intestinal wall much more efficiently with microbes. And given that, that allows them to be recognized much more efficiently, we believe, than microbes. So that could well also, in inflammation, translate to even more potent activity than we've seen with 18-15 or any of the other things we've worked on preclinically. And we don't know how far that could go. In the best case, we could maybe get antibody-like activity with EVs and inflammation, which obviously, Roger, would be beyond transformative. So we're very excited about EVs. We'll get the data next year in inflammation. We'll go into the clinic we expect with confidence in inflammation and in oncology. The steps are very much in line with what we just talked about in atopic dermatitis. As your question suggests, the challenge is to manufacture something which has never been manufactured for pharmaceutical use before. The fundamental first part of the process is still to ferment and produce microbes. And then from the microbes, essentially, we have a process which forces production of microbial extracellular vesicles. And then those microbial extracellular vesicles are essentially, through filtration, isolated and then, again, converted in a very similar way to drug substance, with the end product being a tablet or capsule containing the microbial extracellular vesicles. Chan, again, who heads up TechOps, as he's always done, has done a great job on developing the microbial extracellular vesicle manufacturing process. And with our partners, that tech transfer and scale-up is underway. We're already at a place where we're very confident that there's not going to be any unpredicted issues there. We'll be able to scale up and do the relevant tech transfer. It'll take a little bit of time, Roger, so that's what we're going through right now. but it's already well underway. And then we obviously have to go through regulatory interactions and so on. Again, that's all anticipated for later this year. We're not anticipating any fundamental challenges. Again, these are very much linked to the microbes we've already talked with regulators and others about. So those are the fundamental points on EVs. Hopefully that answers your question.

No, that's very helpful. Thanks for the answer and very informative background information. I believe it's very beneficial for the audience. Thank you. Thank you for taking the question and congrats for the progress.

Thanks a lot, Roger.

Thank you. Our next question comes from Matthew Luchini with BMO Capital. Your line is now open.

Thanks for taking the questions and congrats on the progress. First, I guess, in the context of 1815 and the upcoming psoriasis data, you've spoken a lot over the past several months about Tesla as kind of being the best comp, but now we're in a post. We've got the TIC-2 data. Just wondering if you could share your views, your latest views, your latest thinkings on the competitive landscape, and if you still view Tesla as the best or most relevant benchmark for when that H2B data comes out, and if so, why? And then I have a couple of follow-ups after that. Yeah.

Hey, Matt. Good to hear your voice. So, yes, this is the answer to your question, and let me explain why, meaning, yes, we see a TESA as a key benchmark. Fundamentally, as you know, Matt, the psoriasis space is segmented from a conceptual perspective, into terms of mild, moderate, and severe patients. And we have always said, as an entry point, we want to tap into the moderate and milder forms of psoriasis, and then we'd expand over time into use and maintenance, potentially into more severe patients. Potentially there's even standalone use there, and we'd expand in the other direction to very mild patients. In the true moderate patients, and obviously the lines between mild, moderate, and severe are somewhat artificial, but true moderate patient population, which is millions of patients in the U.S. alone, we do not believe in general will be the target of TIP2s, actually, and we don't believe there'll be significant uptake there. And the main reasons for that are, again, these are millions of patients, are ongoing question marks around the safety of JAKs, and that includes TIK2s, there's potential for black box warnings, et cetera. We don't know what's going to obviously be defined by regulators, but what we do know, and everybody knows, is there's a history of serious side effects and safety and tolerability issues with the broad cast. Dermatologists are extremely conservative in their prescribing practices. There's not a situation where we're treating patients who've got late-stage cancer. And so safety and tolerability is absolutely key. And that's also true for the patient. So we'll see what happens with the TIC-2s, but we don't see them as our core competitor. We think they're going to be used primarily in for more severe moderate patients and in severe patients, as opposed to the broad moderate class. So that then leaves us with Atesla as still the key oral drug. Atesla, by the way, still also is used, despite the fact it's already clearly on the path to being a multi-billion dollar drug, it's only used in a small fraction of patients with moderate psoriasis. So, two things. We do think a Tesla is the benchmark. It's established and has tolerability issues, depending on which numbers you look at, around between 10 and 20% of patients have serious GI tolerability issues with the Tesla. But it's reasonably safe in the mind of dermatologists and patients, and they're used to using it at some level right now. So, So we do think a Tesla is the benchmark, but what I point out is the same comment I made about the TIC2s. A Tesla has a tiny fraction of the moderate psoriasis patient population. That's true in the U.S., and it's even more true as one goes globally. And as you know, Matt, one of my favorite points is there will soon be 10 billion people on the planet, of which only a tiny percentage will be in the U.S., and our strategy has always been to develop manufacture and distribute to patients on a global basis. And we're able to do that, we believe, as we go forward, because we can also produce on a very affordable basis, and that's part of our anticipated pricing model. So we expect we're going to get dramatically higher uptake from a volume perspective than a Tesla's done. So I wouldn't think of us as taking share away from a Tesla. I think about us as creating a massive new market where there's huge unmet need for oil.

Okay, great. Thank you. That's helpful.

And

On the Phase 1B, the formulation study, I guess, what do you expect to communicate and also in kind of what forum, meaning press release or medical conference, for that data? And what in particular do you want us to be focusing on?

Yes, for the Phase 1Bs, I expect we'll release it through a press release, Matt. We'll probably release it as a combined integrated set of data because those Phase 1Bs, as Jonathan mentioned, in an integrated manner are aimed at helping us define what's the best formulation, what's the best concentration, together with the Phase 2s, what's the best dose, as we anticipate moving towards phase three studies. And so what we want to do is just look at all of the different things across those parameters through the phase one B data together with the phase two data. And so we expect we'll report it out, certainly the phase one Bs in an integrated manner so that we can clearly communicate to everybody why we're choosing whatever it is we're choosing for moving forward towards phase three type studies.

Great. Thanks. One last one before I get back in the queue. So with 1867 and atopic derm, you've got the phase 1b come in 4q. Assuming success there, just how should we be thinking about the development strategy between 1867 and 1815, specifically in atopic derm, given that obviously 1815 will be just starting at phase 2 and in the third quarter. So I guess what's the sort of mid to long-term plan for these two products?

Yeah, it's got to be data-driven, Matt. You know, we sometimes talk internally about the fact that a lot of people will sometimes ask us, you know, what do you do if they both look great? And the short answer is we say, fantastic, what a wonderful position to be in. So we have to look at the data, Matt, and there's lots of different ways in which we can develop to the degree they both look good or one of them looks good, the other looks very good in atopic dermatitis. There's lots of different directions we can go, and we'll make that decision driven by the data. The one thing I'd emphasize is that, again, you know this, Matt, from our historical conversations, but we chose atopic dermatitis and psoriasis from our earlier strategic work as the key initial indications and information for a number of reasons. One is the point that I made linked to your original question, which is the majority of patients who have moderate disease in psoriasis and atopic dermatitis do not take oral medicine today. That's true in the U.S. Again, it's even more true globally. So it's just a massive unmet need. So that was one reason. The second was, as we've demonstrated, rapid path to clinical readouts and very informative clinical readouts. And you can literally see improvements in lesions, straightforward things to look at. And then a rapid path to approval from about the state we're at now. It's very rapid, predictable, and if we get positive phase 2 data, it's hard to conceive of a situation where we're not likely to get approval. So all of those things are particularly attractive. But the other reasons we went into psoriasis and atopic dermatitis are that they are rapid ways to read out on the different types of T cell-driven inflammation, meaning cutting across THC. 17, TH1, TH2, together with the experimental model of inflammation, the human delayed type hypersensitivity model we looked at. So across atopic dermatitis, psoriasis, and that human experimental model, we get insight into those different types of inflammatory disease. And again, depending on the data we generate, we can make decisions about where do we want to push one product versus another. But don't think about it in terms of just atopic dermatitis and psoriasis, Matt. As you know, we expect our product will have broad utility across all inflammatory diseases and, indeed, diseases which have inflammation as a core underlying driver. So there are many different directions in which we can go. We'd love to have two products that are looking great. And as I said, it will be data-driven.

Great. Thank you for taking the questions.

Thanks, Matt.

Thank you. Our next question comes from Matthew Harrison with Morgan Stanley. Your line is now open.

Good morning. Thanks for taking the question. I guess there are two from me. Just one question on COVID. Could you maybe comment on what the statistical bar is at the 125 patient interim? I realize given the questions around enrollment, it's going to be hard to say when we might get that, but I'm just wondering what that is. And then I guess the second question is on some of the questions you've already gotten on psoriasis. And I guess the real question here is you talked about looking at Tesla. You talked about CIC2, obviously, in terms of the data. I guess maybe just a very specific question in terms of, what do you think is the right cross-trial comparison that people are going to look at? I realize there's issues with that, but people are clearly going to do it. So maybe you could just give us your review on what you think is the right comparison as we think about the various data sets that are out there. Thanks.

Yeah. Thanks, Matt. So let me take the questions in reverse order. I'll let Jonathan take the COVID question in a moment. But on the comparisons of what people should be looking at, As you know, AAD was last week, and there was new data presented on a Tesla in mild and moderate. And let me just lead with that, because interestingly, there wasn't any data presented on PASI scores. One can read whatever one wants to in that context, but that would be the normal thing that one would be looking for is what's the difference in PASI versus placebo data. in the latest data on a TESA, they haven't reported out on that, which is interesting. But that would be one thing to look at. The other is PGA, where increasingly I think people are very focused on what percentage of patients have a zero or one, so clear or nearly clear skin. And then the last is, in terms of key indicator, is I think increasing focus on patient reported outcomes and things like DQLI, which integrates itch scores as well as sleep scores. And I think those are the parameters. And I think it's looking at those three different parameters in an integrated way together, obviously, with the safety and tolerability map. And as I said, we're intrigued with the fact that there hasn't been a readout on PASI from the latest of Tesla data. There is a readout on PGA. So I think that would potentially put a little bit more emphasis on PGA, but we'll measure both. There is historical readout on a Tesla in a Phase 2, but we don't have it in a Phase 3 yet. I don't know if they'll release any more data soon. And then there has been readout on DLQI, which people are used to looking at. So I think those will be the three major blocks. There's a series of additional things that people measure, as you know, and we'll measure, as Jonathan said, all of those different things, but it's going to be those three main blocks. Is that a helpful answer? Yeah, thank you. And then, Jonathan, do you want to answer the COVID question?

Yeah, I think, Matthew, the only thing I would add there, and we'd be happy to take it offline and talk with you, I mean, the tactic e-study is being run in the UK. You know, in terms of the full type of analyses we'll be looking at, it's the data that I mentioned early on in terms of progression rate analysis. you know, mortality, things of that nature. But, you know, we could go into that with you offline if you want to know a little bit more about the statistics behind that.

Okay. Got it. Thank you.

Thanks, Matt.

Thank you. Our next question comes from Joe Thon with Cowan & Company. Your line is now open.

Hi there, thank you for taking my questions. First one on the atopic dermatitis data for 18-15, now that you've had some time to sit with these results, and I understand there's not a huge patient population here, but is there anything that you've been able to tease out in terms of those that maybe have a more robust response? versus those that don't, and any implications that has to the enrollment criteria for the phase two. And then the phase two is going to have a small proportion of severe patients, I think, if I remember. How are you thinking about potential background therapies in that study?

So again, I'll let Jonathan answer the question about details, including background therapy and so on. On your first point, Joe, in terms of teaching out additional information, we obviously continue to look at individual patient data exactly as you're suggesting, and we'll always look to see if there are learnings, but I think fundamentally it's too small a number of patients to lead to any shift in terms of thinking. We do absolutely look at the individual patient data and see if there are directional things that one might interpret it. It's something we talk about a lot, but there's nothing given the small size of the study that we see as changing anything that we thought of before. And then, Jonathan, do you want to talk about background therapy that we're anticipating in the Phase 2 and atopic dermatitis?

Sure. So for the Phase 2 atopic dermatitis study, in terms of background therapy, participants in that study will be on emollients. So we'll have a two-week lead-in on emollients where we'll have all the participants take their two weeks. We'll rescreen them and then enter them into the trial. So it will all be on the background of emollients that we're looking at. And as you mentioned, we'll be exploring mild, moderate, and the severe population.

Great, thank you. And maybe just one more, just because pruritus and obviously itch scores are important for atopic dermatitis. You did indicate there was benefit in the phase one. Can you just give us a little bit more information there in terms of kind of how robust the itch response was in those patients? And once they were off therapy, we saw some well-maintained responses on EZ and other measures. Was the pruritus measure maintained as well?

So we've reported out on as much as we're going to say, Joe. So, you know, we reported out on the DLQI score and POEM as complete scores. And within those, they've got, you know, itch and pruritus-related subscores within them. And there was a clear separation. Again, small numbers, Joe, so... you know, too early, which is why we're doing the phase two to over-interpret. But we're very encouraged by what we saw. And there's no more details on what we've reported on.

Thank you very much.

Thank you.

Thank you. I'm not showing any further questions at this time. I would now like to turn the call back over to Simba Gill for closing remarks.

Thanks very much. So... Couple of things. So as I said at the beginning of the call, this is just an incredibly exciting time for us. And as Mark described in his opening remarks, a few years into this journey, we are extremely encouraged by the data clinically and pre-clinically that we've generated. With 1815, we've now seen positive data in five separate cohorts of patients. That's consistent with the The very striking data we've seen preclinically in multiple models of inflammation, where, again, to repeat one of Mark's score points, we're seeing preclinical results consistently as good as best-in-class anti-inflammatories in multiple different models. And we've now also got a much better understanding of the mechanism of action at the cellular level. So you put all of that together, and with confidence, we as leaders have developed I believe we're now in a position where we've confirmed data-driven the existence of the small intestinal axis. I'm an immunologist by training, somewhat ancient immunologist by training nowadays. And even today, very, very few immunologists, I suspect very few Nobel Prize winners, is my standard statement on that, in immunology, are aware of the existence of the small intestinal axis. That's just a remarkable thing that we've uncovered today. something fundamental to governing human systemic biology. But what's really exciting is we've essentially demonstrated now clinically that we can harness that newly uncovered area of the small intestinal axis to drive clinical signals. So we're just working through optimizing that in the way that one always does with classic drug development. Great to have Jonathan join us. Great to be expanding the team more broadly. But Mark mentioned that he and I go way back to the very early days of antibodies. And what we've done to date has been much, much faster than what was required in the antibody world, which we're delighted about. And, you know, we're going to have ups and downs always that way in drug development, but we're really well positioned to get there in a very big and transformative way. So I just wanted to emphasize this incredibly exciting inflection point, and we're into 2021 with a lot of confidence. And then, as always, I wanted to thank all our investors and a great analyst for the coverage and the interest in the sport. And no other comments from me. Thank you very much, everyone.

This concludes today's conference call. Thank you for participating. You may now disconnect.