Noon, everyone. Welcome to our healthcare conference. My name is Yaz Rahimi. I'm a senior biotech analyst here at Piper Sandler. Really excited to have the team from Korro Bio here. Pleasure to have you. First, I want to congratulate you on the regulatory clearance, as well as the initiation of your clinical program. You're a clinical stage company now. Yay. It's been an awesome year. So I think it would be great to just kind of give an update on the study design. It's listed on ClinicalTrials.gov in terms of how many doses you're wanting to explore, the type of patients you want to enroll. Maybe start there.
Go for it.
Okay. Thank you. So thanks so much for having us, Yaz. So yeah, you're right. We have clearance to proceed. And Australia is our first country and jurisdiction. So the team is really excited, and they're really in the thick of start-up activity for this program. So we are planning a single ascending dose and multiple ascending dose study in healthy volunteers, as well as patients with a ZZ genotype. So part one is the SAD, and part two is the MAD. And the designs are a little bit different, and I'll walk you through some of our thinking and why we chose to do it this way. But for the SAD portion, we will have a double-blind placebo-controlled design, where we start with healthy participants and then rapidly go into the ZZ genotype patients.
The reason to start in the healthies is so that we can quickly get initial safety and PK data that helps us to select the correct dose to go into the ZZ genotype patients. Because this is a rare disease, there are few patients. We want to make sure that whatever dose that we start them in is efficacious, so that's the thought behind that particular design. We also have a placebo-controlled part, one of the studies, and the reason is because of the scientific rigor, so as you know, a placebo comparator is the best way to assess the safety in a phase I study, and so we have that employed in the part one, and so we'll start with the MMs, single doses, assess the safety and PK, rapidly go into the ZZs for the single dose.
And then once we look at the collective data from the SAD, then we'll select doses to go into the MAD. The MAD is open label. And the reason is because we want to make sure that every patient gets the opportunity to receive drugs. We will look at two different dose regimens in the MAD. And the dose regimen will be informed by the PK data and the safety data that we have in the SAD. And we're going to expand beyond Australia. So we'll have other jurisdictions participating potentially in the MAD, but definitely in the SAD, but definitely in the MAD portion.
How many sites are you planning to activate in Australia?
We have our first site activated. We have another site selected. We may add another one or two sites in Australia. We're looking to see if we need a total of four sites in Australia, or whether we can go outside that country and try to include, because we've had a lot of interest, and there's been a really positive sentiment. There are sites that already have patients sort of lining up, waiting to participate in the study.
Do you envision, in terms of disclosures, to report the SAD data and then the MAD data? Or is there a process to wait concurrently for both of them to come?
Yeah. So we anticipate dosing the first participant in the first quarter of next year. We also have disclosed that we'll have interim data readout in the second half of next year. That's going to be for the SAD. So it'll be a combination of all the data that we have for both healthies and ZZs in the SAD. The MAD will likely also have started by that time and will complete in 2026. So there'll be a separate disclosure for the MAD data. I think it makes sense to, once we have data from the SAD, I think there'll sort of be a needed disclosure that we'll be able to talk to people and also help to garner more interest for the MAD as well.
Okay. Maybe for the healthy volunteers, how many healthy volunteers versus ZZ patients are going to be involved? Because I think the total size is like 64 patients, right? 64 healthy volunteers, o r 64 total. So what is the split between healthy volunteers versus?
So we have a total of 64 participants for the entire study, the SAD and the MAD. We'll have more patients in the SAD combined than in the MAD. And we haven't said exactly how many in each cohort or even how many dose levels. We're only going to use as many healthy volunteers as we need to be able to get to the ZZs quickly. So more to come, definitely, when we disclose the data.
Okay. So then for the SAD data that you're running in healthy volunteers, and the MAD will also be in healthy volunteers, right? Or no, just the SAD? Just the SAD.
Just the SAD. The MAD will be open label.
Okay. So then for the SAD healthy volunteers, how many dose cohorts are you potentially exploring? Yeah. Because he's like, do not answer.
Up to six cohorts, b ut we may not need all six.
Okay. Got it. And what do we want to see, right, when that disclosure comes, whether it's four doses or six doses? What do we want to, what is our expectation? Yeah.
Yeah, so just to clarify, the up to six dose levels will be explored in the SAD, but we don't need six dose levels in ZZ participants, so the ZZs will be fewer than that. I think with any first-in-human study, the first thing you want to establish is safety. We want to show that this drug, KRRO- 110, is safe, that it's well tolerated, that we don't have any infusion-related reactions, that we don't have any safety signals. We want to look at the PK and a number of compartments. And so the PK in the healthy volunteers will help to guide our dose selection for the patient portion. And then, obviously, we want to also look at initial pharmacodynamic data. And I think top of mind for everyone is total AAT and M-AAT levels. So we'll be looking at total protein levels, M protein, Z protein, looking at those ratios for different dose levels in the SAD for the ZZs.
Okay. And is there other preliminary assessment that are going to be done in the liver, in the lung, even though it's too early to assess that in the open label portion? But is there other incorporation of some exploratory endpoint?
Yeah, so that's a very good question, so for the SAD, the focus really will be on the PK and safety and initial pharmacodynamic activity. For the MAD, where you have multiple doses and we're going to reach a steady state, there's more of a potential to look at other exploratory markers. I think it's going to make more sense to talk about exactly what those are at the time of data disclosure, so we'll definitely share more of that detail when the time comes. But we will be looking beyond protein levels in the MAD.
Okay. And then, team, I think that maybe just and that data for the SAD is back half of 2025.
That's correct.
Okay. We'll have plenty of time to bug you with more details between now and then. Yeah. I guess I think that investors are just trying to understand right now. Clear that we have minimal data on hand for Wave release. There's definitely a lot of validation that has occurred for ADRs. But the question that remains is, how does an LNP differ versus GalNAc, right, which you probably discussed in all your meetings today to a great length?
I'll one-to-one test that question.
Yeah. So for people that didn't get to meet you and are just listening to the webcast, just maybe you'll remind us what is the evidence that you guys have been very clear. You generated a GalNAc product, an LNP. You tested it head to head. You chose LNP ahead of it. But just walk us through, because it's opaque for investors. You don't really know how to differentiate it.
I'm going to let Ram speak.
Yeah. That sounds like a good idea. I feel like he has a good answer well prepared. Yeah.
Listen, I mean, I think that when you so when you step back, part of the reason how we ended up with the lipid nanoparticle was keeping the patient in mind, right, and getting to protein levels that are therapeutically relevant, that are as close to normal as possible, normal as an individual. And knowing that this is a novel modality, we wanted to give it the highest likelihood of success, right? And so knowing that there's a large amount of transcription happening, the best way that we knew how to deliver a large amount of oligo was with a lipid nanoparticle. We went through and tested out a bunch of providers to look at which would give us the highest safety window, efficacy to tox, and identified Genevant as the provider that we in-licensed the technology from and built KRRO-110 around.
I think the consideration of the lipid nanoparticle has two other components to think about. One is you asked about impact on the complexity, the rapidity of action for that product. We'll be able to see very quickly the peak amount of protein levels that you would get, even with a single dose. And we demonstrated that in our preclinical studies, demonstrating that as early as three days or so, we could get peak editing, at least in the mouse models. And that has translated to a greater than 50% editing, AAT-related, translating to protein. The second consideration is that what we're seeing is that with this construct and with the Genevant lipid, we're able to dose much higher relative to even Onpattro, when you think about their label, their 0.3 mg per kg. They've shown animal data at 0.3 mg per kg.
We've shared data with no changes in the liver function at 2 mg per kg. So we have a pretty large window in which we can actually dose from a tox profile that we can take into the clinic. And so between those two, I think we think that we'll be able to achieve the therapeutic levels that we would need, both from a regulatory standpoint as well as from a patient standpoint. I think one may ask, why do you need such high levels of protein or normal protein? Well, there are two reasons. One, for the lung, you know you need to hit at least 50% editing to get to therapeutic benefit. But the second component is the liver. You need to be able to remove as much of these Z proteins from within the hepatocyte.
So higher is going to be better to provide and see efficacy early in the liver. So we believe that the lipid nanoparticle at the current moment, when we made that choice, was the right thing to go after. And we always had in the back of our plan from a lifecycle management, I think last time we discussed this, to come back once we see patient benefit, once we know the therapeutic protein levels that we need to hit to, we can always come back with the lifecycle management. But for now, I think we think that KRRO-110 is the best way to go. And hopefully, our data demonstrates that.
What do you think about dosing administration or durability? I know we have not really seen nuggets or pieces of Wave. So what do you think their administration frequency is going to look like? What is it going to mean for you from a product profile perspective? Are we going from a, I don't know, once a week to once a month? Where are we? It's kind of also opaque to investors.
I'm going to let Kemi take this one just in the context of I don't know about Wave. We could talk about us.
Yeah. Yeah.
Right now, augmentation therapy is weekly, dosed weekly. It only has an impact on pulmonary manifestations and nothing on the liver. Additionally, in the setting of acute infection or inflammation, because it's exogenously administered, you don't have that normal acute phase protein response where you're having an increase in alpha-1 levels. There's a lot of room for improvement for therapies that are currently in development, like KRRO-110. We believe that if we can get to a monthly dosing frequency intravenously with our drug, that that would provide a significant improvement just on the basis of efficacy, as well as looking at the unmet need with the clinical manifestations of the disease, but also in terms of convenience and adherence, right? Every four weeks has been when we talk to KOLs and talk to patient community. They feel like that would be a significant improvement. We think that there's a reasonable chance we can keep that in clinics.
But just one note. Once a month, but at protein levels that are as close to normal as possible. So achieving once-a-month dosing with a subQ at subtherapeutic levels isn't really going to cut it. You need to first hit the clinical efficacy, and then the convenience comes on board.
So maybe could you talk about, I think it was clear from Wave that they achieved like 10.8 µmol. And I think given your potency, how to get to normal levels, what is the evidence? And of course, you're doing the human studies now to believe that you're going to surpass that efficacy.
Yeah. So I mean, I can start. So if you look at the preclinical data in the same mouse, NSG mouse model, and you compare KRRO-110 to WVE-0 06, there's a significant difference in the editing efficiency as well as the micro- protein levels that were produced after single as well as multiple doses. So if you sort of scale that to humans and what we expect to see in clinic, we expect to be able to, at much lower doses, be able to demonstrate much higher peak levels close to what's considered normal for AAT, as well as maintain a therapeutic level at trough. So the data that Wave disclosed was encouraging and was great for the field. But the total and M protein levels were still subtherapeutic, as you know, right? And so there's definitely room to improve there. That's where we feel that we can fill in that gap.
And then what work is being done or what assays are you using? There's also questions around the feasibility of assays for measuring protein levels and defining the lower limit of quantification. How are you thinking about it? Because obviously, that will be a key measurement in this SAD as well as the open label MAD.
Yeah. I mean, I think that's probably getting a little bit into the weeds in talking about specific assays. But we do expect to use a mass spec, which is sort of standard. And we will disclose what assay we use at the time that we disclose the data.
And then, team, obviously, you've got the regulatory clearance in Australia. What will be the sequence of other, I guess, jurisdictions that you hope to kick off?
So we haven't talked about that yet. And with Korro's history, I think we like to have the data when we sort of have a disclosure rather than talk about something that's hypothetical. So I think that's coming soon. And you'll definitely see additional jurisdictions beyond Australia because we are planning a global study. We're not just thinking about this phase I, IIA, but we're thinking ahead into later stage studies, a pivotal study, right? And it's in our best interest to get sites in different countries up and running right now so that they are used to the company, used to the drug. We have efficiencies, and we can have a really quick startup period for a pivotal study in the future.
Okay. And then, team, as you think about the alpha-1 antitrypsin deficiency market opportunity, talk about sort of how do you foresee which patients would be ideal for KRRO-110 ?
Yeah. So I can start with that, and then maybe you can add to my response. So our initial target population is patients with the homozygous ZZ mutation because those are the most severe. But as you know, heterozygous patients, MZ, SZ, can be symptomatic, especially if they have environmental exposures to allergens, dust, cigarette smoke, et c. And so beyond the initial target population, there is definitely opportunity to expand potentially in a lifecycle management into additional populations. When you look at ZZ patients, as we mentioned before, there's a huge unmet need with respect to addressing both pulmonary and liver manifestations. And then even with patients who are heterozygous, they can progress just as quickly as the ZZ patients. So we feel like there's a broad pool of patients that could potentially be addressed by KRRO-110 .
I'll piggyback that with the numbers that are there, at least what we've been able to find based on discussions with KOLs and physicians and running primary and secondary research. And as most investors are aware, there's about 10,000 individuals here in the U.S. that are treated with augmentation therapy. That probably represents somewhere between 8% and 12% of individuals that have the ZZ homozygous mutation from a prevalence standpoint. Probably another additional 25,000 that are diagnosed but not treated. And so that's the gap between 30,000-35,000 and 80,000-100,000, where once the therapy is on the market, you see that there is benefit, that you're going to see an increase in the total addressable patient pool that will get diagnosed and will have the ability to access them. But as of today, there's like 30,000-35,000 individuals in the U.S. alone that we know exist.
How do you obviously, 2025 is a big year, right? You're going to start dosing your first healthy volunteers. You're going to have data. You're going to start the MAD open label study. It'll be exciting to hear how you communicate around that, too. So we love open label studies. That's great. Is there any conferences, competitive data? I mean, I think Wave has just said they're going to have data in 2025. Didn't communicate beyond that. What are you watching there in terms of updates that it's also unclear when we're going to get the next catalyst there as well.
I mean, we will have a presence in conferences. If we're not ready to disclose data yet, we can definitely talk about a study design. So I think you'll see Korro. But more to come. I think we have to kind of iron out the schedule as when we think that that exact date would be.
Yeah. I mean, KRRO-110 is not the only asset that we're working on, right? So I think that as we set out from a company perspective, there are multiple assets that we're working on. And so when I look back at 2024, late 2023, we nominated the development candidate. We filed and got approved in less than a year. That included running tox studies and manufacturing runs. We're likely going in 2025, we're going to show you a little bit more in terms of what other assets we're working on, what other targets we're working on, and come with data in terms of where the indications are.
I don't think our thesis or strategy from a company build perspective has changed, i.e., show it works in humans at a high level, show that we can create a de novo protein and have benefit, and show activity outside of the liver, right? A second program with a GalNAc conjugate subQ therapy is likely to start sharing data. Then the third one, we'll see how long it takes for us to demonstrate some data sets around there. Let's not forget, we did a collaboration with Novo, right, to go and access patients in large numbers for cardiometabolic diseases in areas of interest for them. It's unlikely that we'd be doing a lipid nanoparticle-mediated IV infusion for millions of patients.
We're pretty excited about the potential there because it is a pathway that we know. Hopefully, we can show some benefit in the 2025 to 2026 time frame. I think 2025, 2026 is going to be a pivotal year. Every year for our company is always critical. By the end of 2025, we'll end up with a global study from phase 1, 2. We're likely going to have visibility on additional candidates, likely to have visibility on progress on the partnership. For any company, that's a big year.
Yeah. Well, you summarized very well. All you guys did great work in 2024, and you have a great 2025 and 2026. So I just want to say thank you on behalf of all of us here at Piper Sandler. Keep doing what you're doing. Yes. And it's been a pleasure having you at our conference. So let's thank the team for a great discussion.
Likewise.
Thank you.