The Bank of America Healthcare Conference. I'm Greg Harrison, one of the mid-biotech analysts here at BofA, we have today Chinook Therapeutics, with Erich Birkholz, CFO, and Andrew King, CSO. Let's just jump right into the Q&A. Maybe start on the atrasentan program. It sounds like you've finished your FDA meeting regarding delaying the proteinuria endpoint from 24 to 36 weeks. Maybe can you talk a little bit about how that meeting went and what was the primary driver of changing the endpoint? A very positive interaction with the FDA and alignment on shifting both the primary endpoint of proteinuria as well as the interim analysis for unblinding the dataset to week 36 from the originally planned week 24, which we thought we had strong alignment with the FDA on. The rationale was really around essentially providing parity across programs. They have two accelerated approvals now in IgA nephropathy based on that week 36 endpoint, and they felt most comfortable applying that consistently to other sponsors. We're pleased to come away from that meeting with clear agreement. All along, we've indicated that either the week 24 or week 36 proteinuria endpoint is supported by the trial design and nothing changes operationally from that perspective. Look forward to providing top-line data in the fourth quarter this year. Great. Yeah, looking forward to that. You've completed the full enrollment of ALIGN and the SGLT2 stratum. How should we think about the refined timeline for expecting the proteinuria readout and any eGFR there and the data with the SGLT2? Yeah. The primary endpoint as Andrew just said, will be in Q4. Consistent with, you know, we had previously said second half, but we'd sort of suggested it wasn't likely to move to Q4, now that's been confirmed. The eGFR endpoint is after two and a half years, that hasn't changed at all. It'll be essentially, you know, roughly two years from now. Okay. Got it. The competitor just got FILSPARI approved in February and they have a liver monitoring REMS requirement. Can you remind us why you think atrasentan may not have the same requirement and when do you plan to engage with FDA on this topic? Launching without a liver REMS would certainly be a potential area of differentiation, and we do think we have a strong scientific rationale to support that for atrasentan. Some endothelin receptor antagonists have been associated with rare but potentially serious hepatic toxicity, although not all endothelin antagonists carry that potential risk. Atrasentan is a low-dose compound, which is a really important mitigator of any potential risk for drug-induced liver injury, has a different chemistry from endothelin receptor antagonists that have previously been associated with or currently carry liver REMS. Probably most importantly, we have a very large safety database of over 8,000 subjects treated with atrasentan for over 5,000 patient years of exposure with no evidence of hepatic toxicity with atrasentan. We plan to take that package and rationale to the FDA in an upcoming interaction to begin that dialogue, present the totality of the hepatic safety data from atrasentan, really understand what they're looking for at the time of submission, and really push forward this rationale that atrasentan doesn't carry hepatic toxicity risk. We'll begin that dialogue. It's likely ultimately to be a review issue when the full data package is available from ALIGN. No guarantees where we'll land on this, but we think we have a strong scientific rationale. Okay. That makes sense. Do you have any thoughts on what we've seen so far with the uptake of TARPEYO and FILSPARI? We got an update last week from them from that launch. You know, any thoughts on those launches, what you're hearing from nephrologists and what that, you know, implies for your opportunities on the road? I think those launches confirm the unmet need in IgA nephropathy, and we're happy to see that things seem to be going well, and we fully expect that that will continue to be the case. We look forward to having the same opportunity, subject to our data, of course, supporting approval to provide our drug into the same market. Great. They also recently had this Travere had their FSGS readout recently. Is this an indication that you're considering developing atrasentan for down the road? Yeah. We are actually currently exploring atrasentan in FSGS in the phase 2 AFFINITY basket trial. It is an indication we think that ETA inhibitors could have therapeutic benefit. It was disappointing to see the recent Travere data in terms of the huge unmet medical need in FSGS. There are some likely important learnings from that which we need to integrate into our overall consideration for atrasentan in FSGS. Most importantly is that ongoing AFFINITY basket trial and the data with atrasentan in FSGS. We have two separate cohorts. Cohort 1 was administered at 0.75 milligrams. We've shared that we've completed enrollment. We observed lower than expected exposures of atrasentan in that patient population, while encouraged by the proteinuria lowering we're seeing with that lower than anticipated exposure. We added an additional cohort to AFFINITY that allows dose escalation to a higher dose to more fully understand the profile of atrasentan in FSGS to make a data-driven decision as to what's next in FSGS with atrasentan. We do plan to report data from that AFFINITY basket trial, likely the FSGS low-dose cohort later in the year. Okay, great. Is there any reasons, you know, just from the chemistry of your molecule where, you know, you might expect to see a different result than Travere had in this disease? I think there's perhaps related to atrasentan being just a selective ETA antagonist, not complicated by the dual pharmacology of sparsentan, which blocks the AT1 receptor as well as the ETA receptor. Both from a molecule perspective, we can deliver atrasentan fully optimized to block ETA, uncomplicated by the ARB component to get the full therapeutic benefit of ETA blockade in FSGS. There's also some nuances in the study design that was required because of that dual pharmacology, including a two-week washout of background standard of care treatment, leading to a large proteinuria response on the control arm, as well as large acute hemodynamic effects when you're starting treatment not on background RAS inhibitor. With atrasentan, the phase 3 study design would be simpler. Really just lay it on top of stable standard of care and test it against placebo. We do think there are reasons from, the potency and selectivity of atrasentan and the study design associated with that could be a significant advantage for us. Got it. What are you hearing and what's your position, I guess, on the potential for having, you know, your approach with an ACE or an ARB that a patient might already be on versus the dual mechanism of the competitor? In terms of uptake, you mean? Yeah, in terms of uptake, you know, which might be preferred or if there are certain groups that... Yeah. I mean, you know, we think it's simpler because 95% of patients are treated with a RASi frontline, and they would be optimized on that. We think it's simpler just to add atrasentan. There's also some physicians, and I'm sure some patients who would prefer one pill over two. We're not saying one size fits all by any means here. We think this is a very large unmet need, large opportunity. Patients are gonna be on therapy for decades. There's room for multiple approaches to be very successful here. Yeah. Yeah, definitely agree with that. Maybe let's switch gears to BION-1301, the anti-APRIL antibody. What should we expect from the data update from the phase 1/2 trial at ERA next month? Yeah. We will have an abstract presented at ERA, which is essentially five-six months of additional follow-up from what was presented at ASN back in early November. That includes additional follow-up in cohort 1, which was fully enrolled at the time, out through extended periods of treatment, and significant additional follow-up in cohort 2, the subcu administration of BION-1301 de novo. There'll be several additional patients in that cohort now that it's fully enrolled, up to 30, with an additional six months of follow-up. The first patients will be out through 1 year of treatment in cohort 2. The presentation will include the data consistent with what was shared previously around the mechanistic biomarkers, safety as well as proteinuria. Great. Then the competitors, Vera will be launching their phase 3 for atacicept soon. Otsuka's phase 3 is underway. How far behind do you think you are, and how are things shaping up for a phase 3 study here? We've announced yesterday that we're on track to start our phase 3 trial mid-year, so we think we're not behind Vera Therapeutics. In terms of Otsuka, they're we're probably 1 year behind, but our trial seems to be smaller than theirs, so we'll see what that means in terms of when these trials finish. Okay. What are the key elements of design here for the BEYOND study relative to ALIGN? You know, fairly similar framework to ALIGN, the kind of the proven strategy for accelerated approval based on proteinuria and confirmation of eGFR. Because the evolving landscape of treatment in IgAN is shifting a little bit, we will allow patients at baseline not only to be on maximally tolerated doses of RAS inhibitors but also on SGLT2 and/or endothelin receptor antagonists as long as they still have one gram per day of proteinuria. There's still a high risk of regression despite the available treatments today. The proteinuria endpoint is at nine months, similar to where we are now with ALIGN, the mechanism of action of BION-1301 in terms of onset and time to peak reductions in proteinuria is longer than for atrasentan, and eGFR at two years for full approval. The study is slightly smaller than ALIGN, just less than 300 total for the eGFR endpoint, based on the treatment effects we've been seeing so far in phase 2 and balancing that with the need to provide a sufficient safety database. Really more similar elements in design to ALIGN and the other phase 3 IgAN trials. Okay. wanted to make sure and touch on CHK-336. Can you provide any additional color on the safety signal you saw in phase 1? What was that hypersensitivity reaction, and what's the path forward from here? In the healthy volunteer study, in the third multiple ascending dose cohort, following the first dose, there was a single event that appears to be associated with hypersensitivity reaction to either CHK-336 or the excipients, which are standard oral formulations. This is one of 66 individuals that have been treated with CHK-336. They responded well to intervention for hypersensitivity with antihistamines and steroids and had an uneventful rapid recovery. We voluntarily paused the trial to investigate this further, to really try and understand in detail what was driving this response and to work out how we might need to make changes going forward to the protocol in terms of inclusion, exclusion criteria, monitoring, and informed consent. We are planning to move forward with an oral presentation on the initial data from the phase 1 healthy volunteer study at ERA in Milan, which will include safety tolerability PK. We've also incorporated a novel exploratory biomarker strategy to assess target engagement. It's likely at that time, as we continue this investigation, that we'll be able to provide additional update on the strategy moving forward. Okay, that's helpful. About a minute left, I wanted to make sure and touch on commercialization a little bit. What is the strategy likely to be for ex- US commercialization and potential partnerships there? Right. We plan to commercialize ourselves in North America. We've already formed a joint venture for China called SanReno. We plan to partner atrasentan in Japan and South Korea and maybe some additional Asian countries. That largely leaves Europe as a TBD. We're currently exploring and trying to learn how IgAN is treated in each European country and what reimbursement might look like. We'll decide after that whether this is something we should commercialize ourselves or through a partner or maybe through some hybrid approach. Okay, great. Well, with that, we're about out of time. I'd like to thank you, Erich and Andrew, for joining us for this conversation. Thanks everyone out there for listening. Thank you. Good questions. Thanks, Greg. Greg. Thank you. Good afternoon, everyone. Welcome to day two of the BofA Healthcare Conference. My name is Jason Zemansky. I'm one of the new healthcare, mid-cap analysts, here at BofA. It's my pleasure to introduce for this next session Dyne Therapeutics. Eric Dobmeier, President and CEO, and Wildon Farwell, CMO. Gentlemen, thank you for being here. Thanks for inviting us. Perfect. Let's dive right into Q&A. Maybe to start more broadly, can you remind us about your FORCE platform, and specifically, where do you see its advantages, especially within the field of muscle diseases? Yeah. Thanks, Jason. First, I'll just mention forward-looking statements as customary. If you have any questions, please refer to our SEC filings. You know, like I think for Dyne, as you may know, it's an important year for us. We've got a couple of really important clinical readouts coming, all delivered from the FORCE platform. FORCE has been designed intentionally for us, our focus on delivering oligos to muscle in a targeted way. This has been a labor of love for the team over the last four years, bringing a novel platform from discovery to clinic, having two readouts, both DM1 and DMD, our colleague programs, in the second half of this year, and we're really excited about bringing that data forward. As far as it relates to FORCE, I think we were very intentional how we designed the FORCE platform to target muscle delivery. As you know, we use TfR1 as the receptor we target to deliver specifically to muscles highly expressed on muscle cells, and that can also be found on cardiac, smooth, skeletal, CNS. We really thought about how we selected and built the FORCE platform. We use a fab fragment antibody, and we use a clinically validated linker to conjugate to payloads that we select to genetically target the basis of disease. It's a really exciting time for us. We have those readouts coming this year, and I think we've got a chance to really transform the lives of patients living with serious muscle diseases, particularly starting off with DM1 and DMD. Absolutely. Well, just taking a step back here, I mean, how does this technology compare to maybe some of the competing technologies out there, specifically gene therapy? Yeah. Wilden? You know, the real advantage to FORCE and this approach is the opportunity to redose, to be able to titrate, to really be able to target the fundamental biology of the disease. You know, gene therapy traditionally it's been described as a one and done approach, but that creates challenges in a disease that's progressive and continues to evolve over time. I think the FORCE allows us the opportunity to really titrate and understand the dose and dose regimen and really evaluate the patients over time. Before coming to Dyne, I worked at Biogen. I worked in the SMA space, developed Spinraza. Clearly, Zolgensma was developed in that space as well. I saw the opportunity to continue to develop the ASO approach there. It's continued to be successful, continued to be an unmet medical need. We believe that same approach can apply to other diseases such as DMD. Yeah. I think the fundamental thesis behind Dyne's origins was can we deliver more specifically to muscle? I think the delivery is a big differentiator for the FORCE platform. Again, we've shown with robust preclinical data across multiple indications, the ability to deliver to skeletal smooth and cardiac, specifically cardiac in a, I think, exquisite and differentiated way. As you may have seen last week, we put out a press release about our presentation coming up at ASGCT around our CNS delivery. We can add that also to the benefit of the FORCE platform. I think those have broad applicability across multiple opportunities for us as we get onto the other side of our proof of concept data this year. You know, where do we take FORCE? How do we leverage FORCE, to really continue to live out our mission? Great. Let's dive into the data a little bit. Switching to DM1 here, you're expecting safety, tolerability and the splicing proof of concept data second half of this year, you mentioned earlier. What should investors be looking for, and what do you think is a win in terms of functional assessment? You wanna talk about ACHIEVE? Sure. ACHIEVE, this is a phase 1/2 clinical trial for patients with myotonic dystrophy. We really have set it up to be potentially registrational. The reason we say that is because it is a randomized, placebo-controlled study. It has three parts such that there is the multiple ascending dose placebo-controlled, there's an open label extension, and then there's a long-term extension. The study is designed to focus on safety tolerability, but then also to evaluate splicing. Splicing is the foundational biology in all of these patients with myotonic dystrophy. We have the opportunity to evaluate function over time in the placebo-controlled portion, as well as the open label and long-term extensions. Our goal is to begin to see change in splicing and then to be able to correlate that change to function over time. ACHIEVE has been designed to be able to do just that. I mean, our goal here is to take the robust preclinical work we've done in DM1 and recreate that in the clinic. Understanding that we believe 30%-50% of nuclear DMPK knockdown, toxic DMPK knockdown in the nucleus, will release those splicing proteins. That'll translate to a 20%-25% correction of splicing, which we know then leads to functional benefit. We've been able to map that out and see that, correlate that preclinically, take the natural history data, correlate that to that data, and if we can then think about in the clinic now showing the splice corrections from the DMPK knockdown to correlated to function. That is the pathway to registration for accelerated approval. The focus on function I think is probably a little bit premature. This is about splicing. We've been very consistent in our approach and our message for the last four years. We were founded as a muscle company. We understood these diseases. We chose the payload to really match the genetic basis of disease. This is a spliceopathy. How can we correct that splicing? In the early cohorts, the proof of concept cohorts, although we wanna get to 20%-25% splice correction in this study, the early cohorts were looking for robust splice correction across the patients, across all patients in this, in the cohort, and also looking at robust splice correction in the splicing genes across that 20-25 gene panel. That's the outcome we're looking for for this year, and the second half of this year. I think function is something that we'll look at later in totality, but we really wanna be able to correlate a splice correction to function for that accelerated approval pathway. Got it. Do you have a sense of, you know, that 20%-25% splicing levels? What does that look like in terms of like specific outputs, at least based on your early models? In DM1, it's a very heterogeneous disease from a clinical phenotype perspective. Again, the foundation biology that's consistent in all is this abnormality in splicing. In a particular person, depending upon their phenotype, they may see improvement in myotonia or weakness, or they may see improvement in different aspects of the disease. It really comes down to first and foremost, what is the benefit in splicing? Over time, in those particular patients, what is their unmet medical need, and how do you correlate the change in splicing to the change in function? Hi. Cameron Bozorg here, member of Jason Zemansky's team. You mentioned the data could potentially support regulatory package. Have regulators specified any thresholds? What are the major concerns from regulators at this point? The conversation with regulators has really, again, focused on splicing and focused on the foundation of the disease. Over time, being able to correlate that to function. I think again, it's there's not a therapeutic that's been approved in this space, we're all learning, and we will all apply those learnings to the data that we collect and generate. We believe in ACHIEVE, we have the opportunity to begin to see an improvement in splicing, even in the first dose. The dose starts at 1.8 mg per kg ASO equivalent. We believe that's a pharmacologically active dose. Even there, we believe we have the opportunity to begin to see a change in splicing. We over time will look to correlate that to function. Can I just maybe add that global regulators are clear that this is a Spliceopathy. That's one thing that's really important. They understand this disease, where it starts and the genetic basis of it. That's something that we don't have to educate on with regulators. I think they're open to, you know, myotonia or other different endpoints that we're evaluating as a potential correlation from splicing to the accelerated approval pathway. It'll always come down to the strength of the data. I think that we have done the work to map this out from a pre-clinical standpoint, what that story and what that disease pathway looks like. What does it seem and what do we get out of the natural history study? How do we correlate that all together and then map that out to the clinical data we get back? That is really, I think, what we have invested in over the last, you know, four or five years to prepare ourselves for this registrational study we designed in ACHIEVE. Okay. Thank you. Let's switch gears to the Duchenne program for just a little bit. Again, you have proof of concept data coming second half of this year. What levels of dystrophin should we be looking for? What I'm trying to get at here is realistically, how much is possible at six months considering kind of the dosing regimen? It's a great question, and wanna be very clear about the expectations out of the DELIVER study for this year. I'll start, and Will, please feel free to jump in. We think about our DMD study DELIVER in kinda two pieces. We have the starting dose cohorts, which in the U.S. start at 0.7 mgs per kg, and ex-US starts at 5 mgs per kg. We think about that as our starting dose cohorts, and then we think about the 10, 20, and 40 mgs per kg cohorts as our dose optimization cohorts. Out of the starting dose cohorts, which is what we'll be reporting the data on this year, we're looking to be as good or better than the standard of care at 6 months, which is Eteplirsen. Eteplirsen showed 0.3% dystrophin at six months. We think we can do that with 25-50 fold lower dose, given four times less frequently. To put that in the dosing terms, eteplirsen's given 120 mg per kg per month, four times weekly. We look at 2.85 mg per kg, you know, once a month is a pretty big delta. That, in our opinion, will validate the FORCE platform. It validates DYNE-251 as a therapeutic and the global franchise for our DMD program. I think what we really are focused on is the 10, 20, and 40 mg per kg cohorts, really trying to deliver transformational dystrophin expression for these patients in that 5%-10% levels at six months. I think we all know how the protein and how eteplirsen and other exon skippers work over time. You see that doubling effect on dystrophin expression out at two years. If we can generate 5%-10% in those dose optimization cohorts at six months, we think that will then translate to a 10%-20% benefit on dystrophin at two years. We think that's transformational for patients. Yeah, absolutely. Gotta press you on this. I mean, regulators have telegraphed a degree of flexibility here, and so any chance to make this a registrational study? Yeah. Well, we can talk about that. Absolutely. Yes. You know, DELIVER, again, in DMD, we know that the accelerated approval pathway is still open. We've had the conversation. We've designed DELIVER to hit that mark, to be able to really deliver the data that the regulatory agencies are looking for. As Joshua just laid out, you know, we believe that we can achieve that very soon in the study. Our eventual goal is to see transformational improvement in dystrophin, to be able to then translate the disease for these patients over time. Yeah. I wanna give our clin dev team and our regulatory teams a ton of credit here because both of these studies are designed to be registrational. We thought about that early. They're also adaptive in design. As we learn and we get data back, we can then plug that into our modeling, think about what we would deem as the registrational cohort of these studies, and we can be flexible in changing dose and dose regimen. In both ACHIEVE and DELIVER, we are looking at monthly or every other month dosing. We have flexibility to really nail down the regimen as well as the optimized dose here for what we will ultimately run within these studies as the registrational cohort, taking that data to regulators for accelerated approval pathways for both DM1 and DMD. Got it. Maybe a quick one on the commercial landscape. There may be, you know, at least one genetic gene therapy available on the market by the time you launch, you know, what are your expectations, what that looks like in terms of maybe first mover advantage and the advantages of force over, you know, gene therapy? We've always assumed that in our DMD program, when we thought about bringing DMD under the pipeline, that at least one gene therapy program would be approved. You know, Wilden has some great examples and experience in the SMA market. We think it's a great analog. Maybe you wanna talk a little bit about that, and I think that's a good representation of what we would expect commercially. I do think that there's some significant challenges still out there. The gene therapy, the microdystrophin versus near full length dystrophin conversation, durability, duration of effect. You know, pre-existing antibodies are something that is out there for patients that have to consider. Also the immunogenicity of the transgene that's kind of come out over the last year now. All of those things make it a clear pathway for exon skipping, next generation exon skipping to have a formidable place in the indication and obviously the opportunity here, but maybe some of your own experience. Yeah. You know, we know that not every patient is gonna be able to receive gene therapy just because of the antibodies or the concerns around the safety risk that is inherent with gene therapy. Then, you know, what we learned in SMA is that there was still unmet medical need, and that was in a disease where it's a small tissue, the CNS versus muscle, where the CNS doesn't turn over in a way that the muscle turns over. So I think the field is really understanding that there will be a need for additional therapies other than what one therapy may be able to provide. The other is I just say that, look, you know, in SMA, the SMN protein was the same between Zolgensma and Spinraza and the others. Here we have microdystrophin versus a more full length dystrophin. There is potential additional benefit with that as well. Great. Maybe just one final quick question. I think one of the more overlooked aspects about the company and the story is that, you know, there are a lot of applications beyond some of the muscular dystrophy type illnesses that you're currently treating. Mm-hmm. You touched upon CNS earlier. You know, any thoughts into what other diseases you might be looking for at this point longer term? I'm really excited, and I know we all here at Dyne are excited to bring this proof of concept data in DM1 and DMD in the second half of this year. We really are looking forward to talking more about on the other side of that data, where we could apply force. As I mentioned, you know, we see really kind of exquisite delivery to the cardiac. We see CDS delivery. We see additional indications in neuromuscular, where we can go after deep in that pipeline and our expertise. How we do some of those programs internally, externally, how do we think about, you know, reaching patients globally with the global DMD franchise. Not just exon 51, but 53, 45, 44 and others. All that stuff is, I'd say stay tuned. Also our update on FSHD will be coming second half of this year as well. It's, it's a really exciting platform. I think it's incredibly differentiated. It's been a very consistent message in our approach for the last four or five years, and it's now getting time to see the clinical data come back. Once that's validated, I think it's gonna be a really exciting opportunity for the company. Great. Well, perfect. Thank you so much for joining us this morning. Thank you everyone for joining us as well. Yep. Thank you.