Evelo Biosciences, Inc.

very interesting and would in principle support potentially going to later stage clinical trials. Obviously, if we see something at a lower level, then it potentially is still interesting in terms of supporting activation of systemic immunity consistent with what I've just described. So that's what we're waiting for there. Let me pass over to Mark who can talk about maybe I'd suggest Mark do the EV response first and then you can respond on neuro-inflam and if there's anything you don't get to, Duncan can talk about neuro-inflam. Sure. Hello, Chris.

Mark here. The drug product is a natural component of the fermentation. It's the part we normally throw away because the extracellular vesicles are shed from the bacteria into the medium. Rather than harvesting the cells, We harvest the medium and we purify it by a mixture of centrifugation and filtration. It's fairly straightforward. I'm going to answer your questions about purity and content in a regulatory context because I suspect that's part of what you have in mind in asking it. And we have discussed these questions with regulatory authorities both in the U.S. and in the U.K. with very positive outcomes because they recognized that the extracellular vesicles were part of or likely to be part of the types of products that we are already using in the clinic as whole microbes. So actually the preclinical development requirements we have for EVs at the moment don't look to be any different for the microbes, which is hugely beneficial because as you'll recall, we haven't had to do preclinical toxicology testing. And because these are natural products, orally delivered, the requirements for purity are completely different than they would be, for instance, if we were making a mammalian exosome and trying to inject it intravenously or by some other parenteral route. So there's a permissive path for these things that are the same as for the microbes. One other comment about the drug product itself, if we look at dose yield per liter of fermentation, which is where essentially the cost and scale issue will come, it's pretty similar for the EVs as it is to the whole microbes. It actually may be a little bit higher. So we haven't changed our manufacturing scale requirements. It just changes the downstream processing a bit. And then content. So the EVs basically grab parts of the macromolecular content of the parent bacterium. It's not a one-for-one matching, and we're doing a lot of omics at the moment to try and look at that. But, of course, we get a hairball of data showing that some bacteria some proteins are more highly represented in the EV versus the bacterium and the other way around. And we're looking at glycol lipids and, and, uh, and the rest. Um, and, uh, you know, the, uh, the differences we're seeing in the efficacy, which you'll see, uh, in the city poster shortly between the whole microbe and the EV, um, maybe due to differences in content. I suspect it's more to do with the pharmacodynamics of the EV and its ability to get to the target. So that's where we are with that. I hope that answers your question there.

Yeah, and I'm sorry, Mark, but maybe just a very brief clarification. And it's basically, it's a lyophilized product in a capsule. Is that the dosage form? Yes, sorry.

Yes, it's a lyophilized product. It takes a lyophilization the same way that microbes do. We're looking at all the same formulation questions with the EVs that we are with the microbes and actually transferring the technology straight over. There are differences in dispersants and lyophilization excipients and things, but it's fundamentally the same process. Okay. Wow. That brief thing on the, you know, it's very exciting. Actually, it's extraordinary if you think back to where things were four years ago that we were able to reduce it to something like this. It's really transformational. We'll talk more about some of the scientific details behind this in the coming months as well. It's really, it's a new world. On the neuroinflammation, the key point there is actually the one I made a moment ago on the formal part of the call, that the activity of the microbes in the small intestine bypasses the need to cross the blood-brain barrier because syntax, the small intestinal axis does it for us. And we haven't put a lot of these data in the public domain, although some of it is published by our collaborators at the Mayo Clinic. We can clear inflammatory cells from the central nervous system as you can take spinal cord sections. You see it very clearly. And that's a profound statement. Actually, that statement alone would be enough to base an entire company on with the prospects for doing something. And there are companies that are actually based on fundamental ideas about how you can get pharmacological activity in the central nervous system. And that's what we do. It hasn't been part of our mainstream development yet, but it has been a significant part of what we've been doing preclinically. You asked the question specifically in the context of EDP1815. Actually, the preclinical models are ones where we've seen some differentiation in the robustness and maximum efficacy of different microbes. And so we have two other microbes which actually have superior pharmacology in the preclinical models to EDP1815. EDP1815 works. part of its basic anti-inflammatory activity, but these others give us more consistent and robust activity. We'll talk about that more as things develop. So interestingly, as we go out from core inflammation to neuroinflammation, and actually I mentioned metabolism as we look in some of the inflammatory aspects of metabolic control, we're starting to see some degree of differentiation amongst our product candidates that we didn't see just looking at core classical inflammatory models. Okay. I'll leave it there.

Okay. Well, that's, I mean, honestly, just very exciting, obviously, all the work you're doing in the back end. And, of course, we have an exciting year of clinical catalysts upcoming, too. So, anyway, thanks for taking the questions, and great to see the progress. Thanks, Chris.

Thanks, Chris.

Thank you. And our next question comes from the line of Joseph Stone with Cowen & Company. Your line is open.

Thank you. The first one is on the atopic dermatitis programs. When we see data from 1815 and 1867 next year, please remind us how you're thinking about moving forward in the indication. If both look good, would you move both forward or would you make a decision before further committing in the indication? With the data from the COVID-19 studies, if this looks effective here, do you believe there's a role for 1815 in other pulmonary viral conditions? And will this be an area of focus outside of COVID if the data looks strong?

Thanks, Joe. So on the first question, a strategy has always been to look at different microbes, which are differentiated in terms of, for example, in the inflammatory space, how they're driving inflammation resolution and are different in other ways linked to manufacturing, linked to behavior in the small intestine and the gut. And that's why we're taking 1815 and 1867 forward. So they're different, but they're both very potent in resolving inflammation in preclinical models. The way we sometimes refer to it, it's like looking at antibodies, which are both targeting the same diseases but work on different mechanisms and different pathways. And then the answer to your question is it's going to be devil in the details, and let's see what the data is. Obviously, if 1815 drives potent responses in atopic dermatitis, we're going to move it forward aggressively, and we'll still continue to see what happens with 1867. So we have to see the data, Joe, but at the moment we've got somewhat of an embarrassment of riches in having two very potent anti-inflammatory agents that work on different mechanisms. So we'll see what the data reveals there. On 1815, if we see a response in COVID, as your question suggests, it's got very broad utility in a number of other viral infections, pulmonary and beyond, because the core driver of the theory as to why we're looking at 1815 and COVID as you know, Joe, is to resolve the hyperinflammation that causes progression to serious COVID-19. And that same principle of hyperinflammation is relevant to a number of other viral infections, including influenza, for example, which is still killing significant numbers of people in the world, as you know, and a number of other areas. So yes, absolutely, we'll look into other areas if we see positive results in COVID-19.

Great, thank you very much and congrats again.

Thanks, welcome.

Thank you, and our next question comes from the line of Matthew Luchini with BMO Capital Markets. Your line is open.

Hi, this is Jen on for Matthew. Congrats on the progress. Just two questions for me. Could you guys provide some color on what you guys are doing in terms of the trial site expansions, like how many sites are being added, and when they're coming along, coming online, and does that mean there's gonna be a change in geographic makeup of the study in some way?

Hi, Jin. Good to hear your voice. So, let me step back a little bit, and then I'll answer your question directly, Jin. Uh, you know, obviously the world of COVID-19 is complex and unpredictable. What we've been doing to essentially set ourselves up for rapid and accelerated recruitment is exploring, opening up new sites, not just in the UK, but absolutely in other geographies. And we have multiple discussions ongoing right now. As you know, this is part of a UK platform study led by Addenbrookes. Uh, we're working very closely with them, but it's their study. So I don't think it's appropriate for me to say more right now, other than we are looking to expand sites, not just in the UK, but also internationally in some of the obvious areas where COVID-19 continues to be significant. And I expect we'll be able to say more in a not too distant future, Jim.

Got it. And my other question is, could you remind us how the Phase II psoriasis trial helped accelerate development in ADs?

Yeah, sure. Duncan, do you want to take that one?

Sure. Thanks, Jim, for the question. Obviously, there's a lot of learnings that we will be able to take from the EDP1815 psoriasis program for atopic dermatitis. I think, in short, all of the safety tolerability data is very likely to just extrapolate completely across. These are very similar populations from that perspective. Also, from the dose response data, combined with our Phase 1B cohort that's currently ongoing, will provide an awful lot of information, actually, about the dose as well. So we'll be able to take the safety, tolerability, and, in fact, dose efficacy learnings from psoriasis and apply those to the atopic dermatitis program.

Got it. That's helpful. Thank you.

And as a reminder, ladies and gentlemen, if you'd like to ask a question at this time, please press star and the number one on your touch-tone telephone. I'm not showing any further questions. I'll turn the call back over for closing remarks.

Thanks very much, everyone, for continued attention. Attention to what we're doing, as you heard on today's call, this is an incredibly exciting time, both in terms of the clinical readouts we're moving forward, as well as progress in terms of advancing the platform with our extracellular vesicles, as well as progress in other areas of disease and biology. So appreciate the continued attention to Avello, and we look forward to keeping you updated as we go forward. Thank you very much.

Ladies and gentlemen, this does conclude the program. You may now disconnect. Thank you for participating. Everyone have a great day. Thank you. Thank you. Thank you. Thank you. music music Thank you.