Q&A.
Sure. Thanks, Alex. Thanks for having us, and thanks everybody for joining. Oruka Therapeutics is focused on advancing the standard of care in psoriatic disease. Our pipeline is anchored around two co-lead assets, ORKA-001 and ORKA-002. They are both extended half-life monoclonal antibodies, aiming to offer improved product profiles in plaque psoriasis, psoriatic arthritis, and some associated conditions. They are modeled off what we believe are the gold standard in treatment in these indications today, with ORKA-001 modeled off of risankizumab, or Skyrizi's mechanism of action, targeting IL-23p19, and ORKA-002 modeled off bimekizumab, or Bimzelx's mechanism of action, targeting IL-17A/F. With these molecules, we are aiming to achieve dose intervals approaching once a year, so once to twice a year dosing, which we think could be very, very attractive to patients and physicians.
We're also aiming to achieve greater efficacy based on some really compelling clinical evidence for higher efficacy at higher exposures, particularly with the IL-23 asset. We think there's an opportunity here to really unlock off-treatment remission for the first time in psoriatic disease, so extended periods of time off treatment, taking advantage of some really interesting biology around tissue-resident memory cells that lead to recurrence of psoriatic disease. We're in phase II development now with the 001 program. We started phase II studies in the summer, and we're in phase I with the IL-17A/F ORKA-002, expecting a readout from that study around year-end. We're well capitalized with pro forma over $500 million in cash on the balance sheet, which gives us quite a lot of runway through multiple very meaningful inflection points for the company. Most importantly, our phase II readouts for both programs.
Great. Maybe one of the most interesting things about this space, especially when you start with psoriasis, is that the pipeline's pretty empty, right? If you look at psoriasis versus, say, something like atopic dermatitis, there's really nothing in phase II plus development there beyond maybe the tic tus at this point. Why do you think that is, and where do you see kind of that white space today?
Sure. Yeah, we think it's actually a huge advantage for our strategy that there really is not much in terms of new biologics in the pipeline for psoriasis. I think it's partly because we are probably reaching the high end of what we might offer in these conditions. Over the past 20 years or so, we've seen it progress from methotrexate and kind of broad immunosuppressants through to Humira, Stelara, Tremfya, Skyrizi. Now Bimzelx is doing incredibly well on its launch in these indications. I think each of those biologics has been rewarded for successive improvements in the standard of care. There's been a bit of a thinking that oralizing these mechanisms or providing the same kind of efficacy via an oral format was the next phase of innovation. You've seen big investments in those areas.
We're basically taking the other side of that coin and saying, if we could get to a once to twice a year sub-queue injection with the proven higher efficacy of biologics, wouldn't most patients and physicians prefer that over an oral option? We don't see others doing that, so we think it's a big opportunity for Oruka.
Yeah, so starting with 001, obviously based off of the Skyrizi, the IL-23p19, how does the design similar versus different than risankizumab? What are the key elements of differentiation and important similarities, really?
Yeah. Both of these programs are designed to have very similar mechanisms of action to what we consider the gold standard molecules, and that's intentional. We want these to be low biological risk programs, have a very high probability of success. These antibodies today are quite good in terms of their efficacy. They bind similar epitopes on the cytokines. They have similar formats. The antibody engineering is quite different in terms of what it can offer, most specifically in the pharmacokinetic properties of the molecule. We've shown with 001 a 100-day half-life in a human, which is over threefold that of risankizumab, which is around 28 days in human. We can use that to enable much longer dose intervals. We think with 001, we could potentially get to once-a-year dosing.
We also can use that to offer other aspects of differentiation in terms of higher exposures, potentially leading to greater efficacy and this off-treatment remission opportunity.
Yeah. To that point, you just presented data from the phase I of the EADV earlier this fall. Beyond PK half-life, what were the other kind of major takeaways or data points out of that update?
Yeah. The PK properties is probably the largest piece of data from that data set that we presented at EADV, the 100-day half-life, which also showed very consistent profiles across patients. We're very happy to see that. We saw good peak exposures, which give you a sense of bioavailability, which looked very good and comparable to risankizumab. We had target suppression via some PD markers showing full suppression out to the furthest data point we had, which was six months, showing that we can fully suppress the pathway at least that long, probably longer as we continue to accrue data. Also the safety tolerability profile looked very good, which is not surprising given the IL-23 class. Overall, we were thrilled with that data set.
You've also now started your phase II-A study. Can you talk about the design there? I want to get into what we should expect for updates next year as well.
Yeah. Our phase II-A study for 001 we call Everlast A. It's a fairly standard patient population for these indications, moderate to severe plaque psoriasis. It has an innovative design aimed to test all the aspects of differentiation we think we could offer. Once to twice a year dosing, potential for greater efficacy, and this opportunity for off-treatment remission. Our primary endpoint for this study is PASI 100. That's fully clear skin at week 16. To our knowledge, that's one of the first times that's been used as a primary endpoint in psoriasis, so we're excited to push the boundary forward for patients. There's primary research showing the improved quality of life benefit at PASI 100 versus, say, PASI 90, which has historically been used as an endpoint. That's the first piece around efficacy.
In terms of durability of response, maybe the most innovative part of the design is at six months, if people have clear skin, they'll either go on to a six-monthly maintenance, which is sort of our base case differentiation, or they'll be randomized into an arm where they do not receive any additional dose until disease recurs. There, what we want to see is how long these responses last. We think there is a very good chance we might get something like 20% or 30% of people clear two years or more after just starter doses. We think that would be an incredible value proposition to offer to the field.
At the data update next year, when we look at the induction readout at 16 weeks, what does a good outcome look like for you just in terms of PASI 100 rates?
Yeah. Maybe it's to set the context around PASI 100 and how it's trended historically in psoriasis. That's fully clear skin at 16 weeks. Skyrizi offers around 43% if you kind of average studies. It's ranged from 40%-50% as a top end. Placebo rates for PASI 100 tend to be very, very low, 0%-1% across dozens of studies. Bimekizumab, which has the IL-17A/F mechanism, has a higher PASI 100 rate, so 62% roughly at 16 weeks. That's sort of the highest we've seen in the indication for any approach. I think with 001, there's precedent based on some investigator-sponsored work, the knockout study, which was run by Andy Blauvelt, where he went to higher doses of IL-23 and saw 67% PASI 100. That kind of paints the corners of what you might imagine.
I think we believe that 001 could have a very compelling product profile, even at equal efficacy to Skyrizi, given all the other benefits we could potentially offer. We think there's a good chance we could have PASI 100 figures in the 50s or even 60s. That would be extremely exciting to add to that differentiated product profile.
In the context of the knockout study and the higher Skyrizi doses there, where are you with your induction dosing relative to the knockout doses?
It's really nice to be able to design these studies with so much clinical data to kind of guide the way. Oftentimes, you're relying on in vitro assays or animal data to guide your approach. Here, we have this knockout study where higher doses or higher exposures of IL-23 antibody were used and led to higher efficacy. We also have the precedent from IBD. IL-23 antibodies are also approved in ulcerative colitis and Crohn's disease. There, they're used at much higher doses. IV induction in UC leads to exposures several-fold higher than what you see in psoriasis. They're very well tolerated with no additional safety events in those profiles. It provides an opportunity for us to go up towards those higher exposures that we're seeing in knockout.
Everlast is designed to mimic the higher end of exposures that we're seeing in the knockout study, still far below what's used in IBD. We think it provides a great opportunity to potentially offer greater efficacy without any significant risk of increased safety events.
Then the other component of Everlast A will be this longer-term follow-up. How much of that should we expect with the update next year?
We started the study in the summer. We announced in August that we had dosed multiple patients on the study and enrollment's going well. We're guiding to the second half of next year for a data release. We really want to have a robust set of data around both the induction efficacy and the durability of response from this study when we release data, because we think both of those are such important aspects of the differentiation we could offer. If you fast forward a year or so, second half of next year, we should have all subjects in the study past the week 16 primary endpoint where we're looking at PASI 100.
We should have some portion of that cohort out to roughly a year since last dose, and then many more at, say, 11 months, 10 months as you kind of walk backwards from there. What you'll have is basically a maturing Kaplan-Meier curve of how long responses last. It may not be the final word on once-yearly dosing, but we think it will start to build a high degree of confidence around how long these dose intervals could extend.
How long will you follow these patients for now?
Yeah. The open-label extension, so subjects will be eligible to go into an open-label extension at the end of the one-year study duration. That open-label extension is open-ended. In theory, we could continue following those patients for years.
Where does Everlast B fit into this? How does the II-B design fit in relative to the II-A?
Yeah. The primary purpose of the II-B, which will start importantly in parallel to the II-A, we're not waiting for a II-A readout to start the II-B, is to test a few different induction dose levels. It's very important in these indications to justify a phase III dose with some dose range finding in induction. We will test three doses in the II-B, the same dose that we're using in the II-A, a slightly lower dose that we think might also be optimal to give us another option for a phase III dose level, and then a dose that's expected to be lower than optimally effective to establish the kind of range of induction dosing.
Based on the sum of that data, when we get to that primary endpoint on the II-B, which would be sometime we anticipate in 2027, that's when we would conduct an end-of-phase II meeting and expect to choose a phase III dose and design and move forward into pivotal studies.
Is the II-A dose the high dose of the II-B? Is that what you're showing?
Correct.
Okay. So then 002, your IL-17A/F, I guess we're waiting for data imminently, sort of? What are the expectations around timing of your phase I data set?
Yeah. We announced that we'd started enrolling subjects in that phase I study back in April of this year. We've guided to around year-end, which is intentional to kind of give us the option of going in January or so.
This is interim as well, right?
This is interim data. These are one-year studies. You start to get a good sense of what the half-life looks like around the six-month or so mark. We will have that data shortly. We can talk about kind of what's important.
Yeah. This is your IL-17A/F. What does good data look like here in terms of both PK and then safety?
It's a similar story to 001, where the most important readout will be the half-life and the PK profile of the molecule. Here, based on the modeling, we think 75 days could get us to twice-yearly dosing, which we think could be very, very attractive given there's not much long-acting in the 17 class. Almost everything is once a month or maybe once every two months at longest. If it's lower than 75 but still north of 50, we think we could do once-every-four-month dosing, which still would be differentiated. Based on the NHP half-life that we see with this molecule, we would expect to be more in that 75-plus day range based on how other YTE antibodies have translated. Safety tolerability will be important to show here. That being said, it's a small phase I study.
There is only limited sort of confidence you can get around that from that type of data set.
Would you expect to see candidiasis in a phase I like this?
Rates of oral candidiasis with IL-17A/F mechanisms tend to be in the 10%-15% range. With 24 subjects in a phase I, I think that's a pretty small n to build confidence around ultimately what that rate ends up looking like. We'll certainly note anything we see on that front in a phase I.
Then the path forward for 002 here, the lead is psoriasis, correct?
Correct.
How are you thinking about balancing two programs in psoriasis? Why both psoriasis?
Yeah. We get that question a lot. Why both 001 and 002 in psoriasis or psoriatic disease? We actually think it makes a tremendous amount of sense. These are huge indications. It's a diverse patient population. It sort of separates into two subpopulations, where psoriatic arthritis is present in around 25%-30% of people who have moderate to severe plaque psoriasis. That kind of defines a separate subpopulation, where for people with pure skin plaque psoriasis, most physicians prefer an IL-23 inhibiting mechanism. It's one of the cleanest mechanisms in all of INI, and it works very well for the skin disease. It does not work quite as well for the joint aspects of the disease, the psoriatic arthritis. If patients have concurrent psoriatic arthritis, that's when physicians tend to prefer an IL-17 mechanism. It works very well for the skin, also works very well for the joints.
It tends to be reserved for those patients because it does come with some sort of nuisance-level tolerability effects that you'd rather not have. You steer towards the IL-23 if you can. That population with PsA is very large, right? These markets are large enough that it makes a tremendous amount of sense to have two assets so you can offer the best biologic for any person with psoriatic disease. 002, or the IL-17A/F mechanism, also has sort of pipeline and a product potential, with HS or hidradenitis suppurativa maybe being the most obvious next indication. There is also a number of additional indications where that mechanism has been shown to have compelling efficacy.
Yeah. Maybe briefly on HS. You've now announced that you want to go after HS. Can you talk about what the... I guess maybe take a step back. What do you think happened with sonelokimab? Are you worried about running an HS study and running into issues with trial conduct, placebo, et cetera?
Sure. It has always been our intent with the 002 program to pursue both psoriasis and HS. It has always been our strategy to start with psoriasis first and then move into HS. When we look at bimekizumab, I think UCB broke out their sales recently on a recent earnings call. 80% of it was psoriasis and psoriatic arthritis, and 20% was HS. The HS launch was later, and it is probably growing. Sometimes people think of bimekizumab as an HS medicine. It is actually doing extremely well in psoriasis and psoriatic arthritis. We have always thought that was the right place to start with 002. We have always planned to go into HS. Obviously, I think the sonelokimab readout a couple of months ago should be on top of anybody's mind who is going into HS development. I think it was an outcome that nobody expected.
HS endpoints tend to be a bit noisier than psoriasis endpoints. Placebo rates are high. We talked about almost zero for PASI 100. HiSCR 75, which is the most typically used HS endpoint, can reach 10%-20% in the placebo group. You are always subtracting that group from an efficacy figure. That introduces an inherent variability into outcomes. I think in some ways, it was not surprising that the phase III looked different from the phase II. I think what surprised everybody was that one of the phase III studies did not reach statistical significance versus placebo. That is surprising because I think everybody believes that that molecule does have efficacy in HS. It makes you think harder about how you run an HS study to minimize the chance that you see a similar sort of placebo effect.
That is something we are working on very carefully right now, is anything we can do differently in our trial conduct or trial design that could increase the odds that we unequivocally show efficacy over placebo in an HS study.
Have you said when you plan to start a phase II?
What we've said is we plan to start an HS trial soon after psoriasis. Psoriasis, we've guided to first half of next year.
Okay. We talked about the complementarity of IL-17A/F and IL-23. Can you talk about that in the context of 021 and sequential dosing?
Yeah. We think it's a big strength to have both 01 and 02 in our pipeline for the reasons I talked about earlier of being able to offer the best biologic for any patient with psoriatic disease. They have this sort of different profile where IL-17s are a little more potent. They act quicker, right? If you look at like two or four weeks, you see more skin clearance on an IL-17. Some patients really like that. Some physicians gravitate towards that. They do come with a little more complex safety profile versus an IL-23. If you think about the ideal maintenance, it is an IL-23. In some ways, the ideal induction is an IL-17. Potent, acts fast, clears the skin quickly. The ideal maintenance is an IL-23.
The idea with ORKA-021 is, what if we could induce a response with an IL-17 and then maintain it on an IL-23? It's an idea we had. We started testing with our scientific advisory board and some other KOLs in the field and got a lot of really positive feedback. Heard things like, "We've always wanted to do this. It makes a ton of sense. But given these medicines are from different originators right now, you can't get it reimbursed. You can't do this. It's off-label. But I would love to do it if it was available." What we see this as is another way to differentiate. This is a $30 billion and growing market where if we can have the best biologics a few years from now coming on the market, we think we'll be in a very exciting place as a company.
We want to create as many different ways we can do that as possible. We may not end up pursuing all of them into pivotal studies. I think based on what we see in phase II over the next couple of years, the odds that we have something very attractive to bring into pivotal trials will be very high. ORKA-021 just provides another way we could do that.
Is this something that you could do a sort of a phase II study concurrently with some of your phase II- B work? How are you thinking about timing?
Yeah. That's exactly what we plan to do, is in parallel to some of the other phase II work, run a proof of concept study with this. The key thing to show is that a response that you induce with the IL-17 can be maintained on an IL-23, right? There's some anecdotal evidence out there in the literature for this, but it's never really been done in a robust way. We could do that in a proof of concept study. That could pave the path towards later stage development.
Great. You mentioned your cash runway. Can you talk a little about what's encompassed in that?
Yeah. So very exciting that we have multiple phase II readouts coming up, all within our cash runway plus a year. We always do the plus a year because if you have a readout coming at the very end of your runway, well, that's not really a readout that you can get to before you have to raise additional capital. Within our cash runway plus a year, we have obviously the phase I data that's coming soon for 002. We have our ORKA-001 phase II-A, that Everlast A readout, the ORKA-001 Everlast B readout as well, which will be a 2027 event for us. And then the ORKA-002 IL-17A/F psoriasis data, which will also be a 2027 readout for the company. Those all become potential inflection points that could propel the company forward into later stage development.
ORKA-003, when will we learn about that?
Yeah. We have chosen to delay the release of that for a couple of reasons. Maybe most importantly being, we think 001 and 002 should be the company's focus. We think our investors agree with that. We think both of those have enormous potential for the company. We do have a third asset that we are excited about. These spaces are also becoming more competitive, where if you have the luxury of being able to not disclose those for a little longer, that is usually the right thing to do. We have chosen that approach with that program for now.
Great. Stay tuned. Thanks, Lawrence. Appreciate it.
Thanks, Alex. Enjoy that.