Really happy to be here with Avidity Biosciences. So we have Sarah Boyce, excuse me, who is the President and CEO. We have Mike MacLean, Chief Financial and Business Officer, and over there we have Steve Hughes, who's the Chief Medical Officer. Right. Yes. So thank you all for joining us. Obviously, fresh off the heels this morning of an exciting collaboration expansion with Bristol. So I'm going to turn it over to you for some opening remarks, and maybe give us kind of some background on how this deal happened. Yeah, absolutely. Thank you, Gavin, and, and thank you to everyone at the Evercore team for inviting us to your conference. It's a pleasure to be here. We were thrilled to announce this morning the expansion of our collaboration with Bristol Myers Squibb, with regards to targeting the heart. It is exactly the type of strategic collaboration that we've talked about doing. You know, we are a, an RNA delivery company, and we're looking to make a profound impact in people's lives. We've opened up the muscle space, we were the first people to deliver RNA to muscle cells in a targeted fashion. We have three muscle programs in the clinic now, and now we're the first going in and looking at the heart, and delivering RNA to the heart in a targeted fashion. I'm going to hand to Mike, who is our CFO and CBO, who has been an integral part of getting this collaboration to completion. And, Mike, maybe you talk about the genesis of it and some more of the color. Absolutely. Thank you, Sarah. So, this is a really exciting expansion with a known partner for us in the cardiology space. So it does really three things, Gavin. It opens up and squarely puts us in the therapeutic area, cardiology. It also, secondly, allows us to move forward our own internal pipeline programs as we also work with BMS to bring forward their cardiovascular programs as well. Sorry, yeah. The microphone. I apologize. Those who are listening on the webcast, we have a microphone issue. Okay, can you hear me? Loud and clear. Okay, great. Why don't we try again? Okay, so, basically, BMS is a known partner for us, and entering into this expansion of our cardiology collaboration does three things for us. It brings us squarely into the cardiology therapeutic area, which we have already started with a pipeline program of our own. It allows us, secondly, to bring forward our cardiology pipeline programs as we work with BMS on additional cardiology programs. So, we will likely focus on rare and ultra-rare indications, while BMS obviously is going to be looking to broader or large orphan indications that probably are not of interest to us in our business model. And lastly, it actually brings a partner who has capabilities, capacities, and skill sets that will really help us to accelerate our entry into the cardiology space. So in terms of how the deal came together, we've been working with BMS on a single-target collaboration for over two years, and we had been talking to BMS and other larger companies about the idea of collaborating in the cardiology space with our technology. And the technology that we're talking about is focused on the transferrin 1 full-length monoclonal antibody, and the conversations with BMS obviously were quite tight in terms of the fact we knew who they were, they knew what our technology was and what it could do. And after the proof of concept data was announced at AAN back in April, those conversations accelerated, and happily, they've resulted in the deal that we've announced this morning. Yeah. No, that's great. Great explanation. And just to be clear, it, it's the same, TfR1 antibody that you're using inside the clinic, no other modifications, obviously, different payloads? Yeah, so the deal is based on the full-length transferrin 1 monoclonal antibody. Any innovation to that antibody is, you know, something that we would share with BMS, but it's not related to any other type of Delivery Technology. Got it. Any kind of qualitative commentary you can give us on the milestones? It seems like there's a fair amount that's in R&D, and even a slightly lesser amount commercial, which actually isn't all that common. Yeah. So in terms of the economics of the deal, we're quite pleased. I mean, $100 million upfront is very meaningful for us as a small biotech with a great cash runway as before we entered the deal. But this $100 million added to our current cash balance will take us through 2025 in terms of our cash runway. And then in terms of the milestones, again, a $2.2 billion opportunity here, quite significant. And we see the milestone distribution through research, development, and commercial as favorable to us in terms of the fact that there are early milestones in the research part of the collaboration that are, on a relative basis, favorable to us, recognizing what we bring to the collaboration in the early days. Lastly, we actually have tiered royalties that would come to us that are from upper lower digits to upper single digits to lower double digits. Well, we got it. Yeah. No, that makes perfect sense. And you mentioned, too, focusing a little more on cardio indications on your own for rare and ultra rare. Like, just as you're thinking about resource prioritization moving forward, is that where you're going to be focusing next, as opposed to muscle? It's probably still going to be a little bit of both. Just help us understand that. Yeah. So, look, I mean, we're going to have two therapeutic areas that we're working on. You know, in the case of cardiology ourselves and with BMS, so we are still heavily involved in the skeletal muscle area in terms of other potential indications, in terms of innovation of the technology. But yes, we have already started working on cardiology as a you know, therapeutic area of interest. And, you know, basically this deal with BMS allows us to get a more solid base into that effort, but it's both, and also bringing forward the platform and potential other indications and tissue types. Got it. It's still probably a little bit early, but when should we expect to hear next steps, or when the programs emerge from this partnership? So, it's a 5-target collaboration. The one target was the single target of the previous collaboration, so right now, that probably is the front runner. We are going to bring the programs through the research part of the journey, and we will transition it to BMS in the development stage. So BMS will determine when those programs get announced. In terms of our own programs, we've got one that we have on our pipeline now that we have not disclosed the target, and we will probably operate pretty much in stealth mode until it's appropriate to name the target, based on where we are at. That makes perfect sense. Great overview of the deal. Thank you. Maybe it also would be helpful to just remind us, for the preclinical data that you've generated to date, what does the cardiac delivery look like? So the cardiac delivery is in terms of it's using our AOC technology, using the transferrin antibody. What we learned from a lot of our preclinical work for our muscle programs is when we looked at knockdown in a whole range of tissues and delivery to a whole range of tissues, it was very clear that we can deliver pretty effectively an siRNA to the heart, as well as also getting really good tissue concentration in there. So a lot of our data obviously comes from our preclinical work. Yeah. Great. Anything else to flag on the deal that we didn't touch on? You know, I would just sort of pull us back from a strategic perspective, as this is where, again, you see us really leading the field. We've opened up the Skeletal Muscle space by being able to deliver RNAs to Skeletal Muscle, and now we're doing it again in relation to targeting the heart. So it's a great o ne of the things that you can now see is the potential breadth of the platform that we have, but also strategically, how we're going about it and how we're doing it in a very purposeful fashion. Yeah, that sounds great. All right, well, let's switch gears a little bit and turn back to the clinical side of things. Yeah. Starting with, let's go with DM1. Maybe just remind us, for the dose escalation, for the patients who went from the 2mg-4 mg per kg and had the MRIs, are there any qualitative insights you can share around what those MRIs looked like? Yeah. I think it's a pretty simple one to answer, 'cause there was nothing. But maybe I'll have Steve, if you just want to talk a little bit around that process, and the latest update we gave at World Muscle. Yeah, sure. So, we were asked to dose escalate patients, 12 patients, from 2 milligrams per kilogram to 4 milligrams per kilogram, and then to perform an MRI scan within a short period of time after that first dose of the dose escalation, so, within 24-48 hours. So we completed that process. There were no MRI changes following dosing. There were no neurological symptoms following dosing. All those dose escalations were performed successfully, very clean, patients doing well. Several of those patients have now had subsequent doses as well, with no extra difficulties. The other data that we shared at the World Muscle was general safety data across the whole program, going through MARINA and out into the open-label extension. So that was 200 plus doses of at any dose more than 46 patient years of follow-up, and the AOC 1001 really well tolerated over long-term dosing, so we're really pleased to see that. Yeah. Of course, all of the patients that rolled over into the open-label extension, so the 37 of the 38 participants that participated in MARINA rolled into the open-label extension. The patient that had the serious adverse event didn't roll over, they weren't eligible, but all 37 patients that have rolled over now can, are continuing to be dosed, and some of those have been out quite a long time now, well over a year. Got it. It's a good overview. What is the latest status of the discussions with the FDA surrounding all of that data? The discussions with FDA are going really well at the moment, and have now opened up to include our Phase III study design as well, which is really encouraging, and we're really pleased with the progress that we're making there. Yeah. And just wanted to confirm still, any of the discussions around partial hold in the cardiac event, that's still specifically for the DM1 program, correct? Yeah, there was, right the way from the beginning, it's only been affected the DM1 program. The other two programs have been unencumbered. Got it. A question I've been getting recently is, can you just remind us what you saw in terms of any hemoglobin impact or potential for impact on iron transport? So, we've reported for the DM1 program that we did see some patients with mild and moderate Anemia. They were, for the most part, completely asymptomatic from an Anemia point of view. I think we only had one participant that had some mild symptoms. All of the patients have continued dosing within the study and out through into the open label extension study, so it hasn't been dose-limiting in any way. The mechanism is related to the transferrin receptor that we target to get the drug into the cell. In order to get drug in, we have to bind to the transferrin receptor, and then the transferrin receptor gets internalised. So if it's internalised, it's not available on the cell surface to bind iron. That's a transient process. After it's been internalised, it gets resurfaced again. So what we see is a transient reduction in iron transport in hematopoietic cells, and then that happens in the kind of 1-week to 2-week period, and then the transferrin receptor's resurfaced, and iron transport continues, and then we see that the changes in hemoglobin turn around and move back up again. Got it. In thinking about the open label data coming in the first half of next year, anything you want to frame for us, how we should think about that, whether it's kind of number of patients, duration, what we should be looking for? Yeah. I think, you know, we're really looking forward to sharing that. So it will be the 37 people who are in the open label extension study, and it will very much be a look at the functional measures. So consistent with the measures that we've had in MARINA, they're also the same functional measures that track in the DM1 natural history study. So it's looking at those functional measures and over time, as well as also obviously giving an update on safety, because at that point, people will have been on drug for much longer. Yeah. Sounds great. Yeah. Are you willing to say anything about phase lll plans, whether that's, you know, functional endpoint, how you're thinking about designing that at this time, or should we wait for an update on next year? I think primarily wait for an update, and that we are leading the field, so we're pioneering the way. Once we've completed our discussions and have something agreed, then we'll share it. Although what I would say, it's very much focused around functional. As you would expect, we see function, we saw functional changes very quickly in the MARINA study and across a broad range of measures. So that gives us a lot of options from a design perspective as well. Mm, yeah, that's great. And for 1044, changing gears to DMD and exon 44 program, still gonna be a safety update in healthy volunteers by the end of this year. If I did my math right, tell me if I did it wrong. At the 10 mg per kg dose for DMD, that is more or less equivalent to the 4 mg per kg dose for DM1, just in terms of TfR1 antibody. Like, let's ignore the payloads, that is the antibody. So and you're going up to 20 mg per kg in DMD, which would be more or less 8 mg per kg for DM1. So tell me if that's wrong. And then secondly, point being, is this DMD update gonna give us an even better read on safety in addition to what we just discussed? Yeah. So I would say you're about right. The 10 mgs is a little more than equivalent to 4 mgs, but your math is roughly about correct. And maybe, Steve, do you wanna talk around on what people can expect with regards to the healthy volunteer look? Yeah, sure. So the look will be at safety for the healthy volunteers. And just to go back to the first part of the question, well, because we have a platform technology, when we're looking at safety, we're always looking across the platform, as well as on the individual programs for any disease-specific effects. In addition to safety, I mean, safety is obviously very important in terms of bridging across into the patients, and we've already now started dosing 5 mg per kg in patients. So the 5 mg per kg dose in the healthy volunteers has been well enough tolerated to allow us to open up in patients now. And the other thing that we're particularly interested in for this upcoming look is tissue concentrations. Mm-hmm F or the drug. That tells us whether the tissue concentrations that we're seeing or what we predicted, whether we're in the therapeutic range that we anticipated as well. So, so we're very excited to see that data. Yeah, that's great. Is there any reason for the tissue concentrations we can't look back at all the clinical PMO, PPMO data that's out there and kind of make some rough cross-trial comparisons? It's difficult, because the data that's out there to date is for different exons, and different exons have different susceptibilities to skipping. So the tissue concentrations required to skip exon 44, for example, won't be necessarily the same as for exon 51. So there are some limitations there, but within our preclinical work that we've done, we do have an anticipated range in which we think we'll start to see clinical benefits, and that's what we're shooting for. Yeah, that's great. And maybe in the last minute or so, we can touch on, 1020 and FSH- FSHD. For the first half update next year, it's gonna be around half of the patients. Just wanted to confirm, do you know which doses yet you're gonna be showing, and just how should we think about, excuse me, this update more broadly? Yeah. So it, it's an update at about the halfway point in the study. What I would say around for FSHD, we're the first program ever in the clinic to directly target the underlying cause of the disease, which is DUX4. So that is incredibly exciting for the physician and the patient community. And one of the aspects, I think, for that midpoint look, again, looking at safety, looking at delivery, and then also looking at some of the downstream genetic signatures of DUX4. Yeah. That sounds great, and I think we're just out of the time, so it works out well. Awesome. Thank you so much for joining. Really appreciate it. Yeah. Congrats on the update this morning. Thanks so much. Thank you, again.