All righty. Well, welcome everyone.
My name is David Risinger. It's very much my pleasure to welcome Oruka Therapeutics to our session today.
I'm here with the CEO, Lawrence Klein, and I thought it'd be great to just have you start with your vision for the company, and then we'll roll from there.
Yeah. Thanks, David. Thanks for having us.
Thanks everyone for joining. Oruka Therapeutics, our core focus is advancing the standard of care in psoriatic disease.
Our pipeline is anchored around two co-lead programs, both of which are ultra-long acting monoclonal antibodies targeting what we believe are the best two targets in the psoriatic disease space, IL-23p19 and IL-17AF. I think many people are familiar with these indication spaces because they've led to the growth of some of the most successful products, I think, in biopharma, and certainly in immunology and inflammation.
Our two products are sort of modeled off of what we consider the gold standard antibodies today for psoriatic disease, Skyrizi, for as a IL-23p19 inhibitor and BIMZELX on IL-17AF.
We're aiming to differentiate over those kind of gold standard molecules primarily through half-life extension, so a longer lasting antibody in the serum, which could enable really, I think, never before seen kind of dose intervals of potentially reaching once a year with the ORKA-001 program and twice a year with the ORKA-002 program.
In addition to that, we think there's opportunities to potentially have higher efficacy or greater rates of skin clearance, and maybe to offer off treatment remission for the first time in psoriatic disease.
We're testing those aspects of those profiles in ongoing Phase II studies with the ORKA-001 program. We call that program EVERLAST, the Phase II studies. We have a part A and a part B, which are both ongoing.
We'll have a readout from the part A in the second half of this year, which I'm sure we'll talk about. And then the 002 program will enter Phase II studies in psoriasis in the first half of the year, and then in HS, or hidradenitis suppurativa, in the second half of the year. And we're well-funded through all of those readouts with additional capital beyond.
In a very strong position to sort of de-risk these programs and show the potential differentiation that we could have, which I think at the higher end of what we could achieve could really be some very exciting outcomes in terms of I mean, you can have $5 to 10 billion products in this space if you have meaningful differentiation over standard of care.
Excellent. Maybe we could step back and I'm curious to have you talk a little bit about what brought you to the company and why you were hired.
Yeah, thanks. Thanks for asking that. So I was at CRISPR Therapeutics, was my operating role, prior to Oruka. Spent seven years there as the company grew from about 30 people to over 500. I was chief operating officer and chief business officer there.
That was a tremendous experience to get to see a company take new technology from the laboratory all the way to we had the first approved CRISPR-based medicine in Casgevy for sickle cell disease.
I was looking for a next kind of challenge in my career and really wanted to take my time and find an opportunity I was very excited about and heard about this group of companies kind of coming out of Fairmount and Paragon.
Apogee Inspire were the first two, and I heard there was a third company in the works and started to learn more about Oruka. It's got a very different profile from CRISPR, right?
CRISPR is, here's Nobel-worthy science, can we turn it into a medicine? That was very rewarding to be a part of. This is, can we take a combination of well-validated technologies and make a product that could really offer something different to people in a disease that affects millions and millions of people 10 million plus people in the U.S. alone.
Some of these products become some of the most important products in our industry.
I was excited to be part of that on something where I saw an asymmetry in the level of biological and technical risk you need to take in order to achieve outcomes that I think could really be, tremendous.
Excellent. That's super helpful. Why don't we talk about ORKA-001 first? If you just remind everybody what's been demonstrated to date and what you're hoping to demonstrate in the second half.
Yeah. Over the past two years or so, we've taken ORKA-001 from development candidate into healthy volunteer studies. We read out data from those in the second half of last year. We showed a 100-day half-life with that molecule. To our knowledge, that's the longest half-life that's ever been seen with a monoclonal antibody in all of pharma. Pretty exciting.
We think that molecule has very unique properties. Very good tolerability in that Phase I study as well. That enabled us to start a Phase II study. That's the EVERLAST program. We started Part A of that study last summer, and Part B started enrolling in December. Those are going very well in terms of operational progress. The enthusiasm from sites and patients has been, I think, exceeded our expectations.
The team's been executing tremendously well. Very proud of the team we've put together and how quickly we've moved that molecule through to where it is today. We're very excited to be in the same calendar year as our first data in psoriasis in the second half of the year from EVERLAST-A is the plan. We can talk through kind of the aspects that that'll entail and what it could show.
Excellent. Yeah, well, before we even do that, just at a high level, just explain A and B.
Mm-hmm.
We'll go back to A and go into some more detail.
Part A is a single dose level. It's 600 milligrams, week zero, week four, compared to standard dosing of Skyrizi is 150 milligrams week zero, week four. Really the reason for the Part A is we wanted to get as fast as possible to a dataset that shows what this molecule is capable of. You can get a lot of confidence around the dose you're selecting based on the prior evidence with IL-23s, the PK that we had in healthy volunteers.
We decided to go for it with the 600 milligram dose, and we can talk through that that could show potential for once-a-year dosing, potential for higher efficacy, potential for off-treatment remission, all in that one study. We could test all the aspects of differentiation.
We wanted to get as quickly possible to that. In order to select a Phase III dose, you really need to do some dose range finding to satisfy the agency that you've selected the right dose for Phase III, and that's the primary driver for the Part B. In EVERLAST-B, we're testing again that 600 mg Q4 dose. We're also testing a 300 mg Q4 dose, which we think is a very viable dose.
There's a chance that 300 and 600 look similar, and we could take either of those forward into Phase III, depending on what we see. Then we're testing a sort of suboptimal dose so that you can get a full kind of picture of the exposure response to the molecule and justify selection of a dose for Phase III studies.
We want to get to phase three as fast as possible and get ahead towards you know BLA, which is you know starting to put those plans together. So it's pretty exciting.
Phenomenal. Let's talk a little bit more about that readout in the second half, what you're targeting and what we should be focused on.
Yeah, that's probably the most common question we get these days from investors, which seems right. The goal of putting that data out in the second half is to be able to have a fairly full picture of what the molecule can do. We'll have all the patients in the study. It's designed to enroll about 80 patients. We'll have everyone through at least the week 16 time point, and we'll have some portion of the cohort.
We haven't said exactly how many, but some portion out to roughly a year since last administration of the drug. Which also means we'll have more patients as you walk back at 11 months, 10 months, 9 months. The idea there is we'll have an emerging picture supporting once-a-year dosing, right?
We won't have everybody out to the year at that point. I think if you saw a picture where people are staying clear out to 12 months, and then you have more at 11 and 10, it'll start to build a lot of confidence around once a year.
You could have both aspects of once-a-year potential and the efficacy readout in that second half read. That's the aim.
Excellent. Maybe you could talk about PASI 100 and what the possibilities are.
Yeah. We're excited to have PASI 100 as a primary endpoint in that study. We think that's really the goal today in treatment of psoriasis, and it's pretty exciting. That's fully clear skin.
Historically, endpoints have really only gone up to PASI 90 as the goal. This is really pushing the bar forward. There's really robust literature supporting the quality of life difference at PASI 90 versus PASI 100.
Patients really want clear skin, and that's what physicians want for their patients these days. I think we believe that equal efficacy to Skyrizi on PASI 100 would be a great outcome here for ORKA-001.
If we have equal efficacy with once or twice-a-year dosing, potential for off-treatment remission, you take that profile out and you test it in the market, you model what it could do in these indications, you can easily get to $ multi-billion-dollar outcomes, which very exciting for Oruka, could reward all stakeholders.
We've got other ideas following that could then build with ORKA-002 and then the sequential combination and other programs.
That would be a fantastic outcome. At the same time, there is quite a bit of evidence suggesting that these higher doses could lead to higher rates of skin clearance. And the way we think about that numerically is historically, Skyrizi has ranged from about 40% to 50% on PASI 100 at week 16 across quite a few studies, right?
It's been tested in quite a few different studies, and it has been in the 30s a couple times, but tends to range between 40% and 50%, with an average around 43%. The way we think about it, just to keep it simple, is if we're in the 40s, that's equivalent efficacy to Skyrizi, and that's a great outcome for zero zero one. If we get into the 50s, that's better efficacy.
That's better than Skyrizi has historically shown. I think that'd be very exciting. I think the higher you get into the 50s, really the more impactful that would be. I think the high 50s would be extremely exciting. bimekizumab or BIMZELX, which is doing incredibly well in psoriasis, has efficacy in the high 50s to low 60s on PASI 100.
That would start to be BIMZELX-like efficacy in a potentially once a year IL-23. I mean, I think that starts to be a category winner.
I think there's some chance it's in the sixties. I think the knockout study, which tested higher doses of Skyrizi, got into the sixties. By no means is that the expectation, but I think if we had an outcome like that the sky's the limit for a program. I think you could have a $10 billion drug.
Phenomenal. I guess maybe, go into a little bit of detail please just on the safety that you're expecting with that 600 milligram dose at 16 weeks.
Yeah. I mean, I think we should have a fairly strong sort of prior hypothesis that the safety with zero zero one should be similar to other IL-23p19s. There have been five different IL-23p19 molecules that have gone into the clinic in psoriasis and all shown similar safety profiles. You really can't tell them apart. Those are different molecules from different originators binding different surfaces on the cytokine.
We have a molecule that binds a nearly identical surface to risankizumab or Skyrizi, shows similar potency in a variety of assays. As the N of patient exposures grows, I would be very surprised if we end up with a different safety profile than other IL-23p19s have shown. I think with small numbers you can always have things that then revert to the mean as you accumulate more patients.
IL-23 is one of the cleanest mechanisms in all of I&I. Really the only imbalance you see is on upper respiratory tract infections, so things like common cold, which aren't of clinical concern. Really a very safe target.
Excellent. With respect to that potential for annual dosing, could you talk about that and your vision for looking out to Phase III and potential commercialization, just how that might play out in the real world?
Yeah, sure. I mean, we're very excited about the potential for annual dosing. I think that's sort of a new horizon for therapeutics in immunology. I don't think really anything has reached that dose interval before, and it would be extremely exciting to achieve. If you take that out with physicians, you'll hear things like, "That could be a game changer." I think that could be extremely impactful.
Excellent. How would patients be dosed? In the real world, let's say that you have a label for annual dosing.
Not 100% of patients are going to be able to have the duration of effect or have the benefit that they need all the way out to 12 months. Could you talk about your vision for maybe a different paradigm for treating patients?
Yeah, sure. Ultimately we'd want to have both once a year and six-month options on the label.
Mm-hmm.
I think based on the PK that we've seen, we think the vast majority of patients could go to a year with a sustained response. There may be some patients who need a six-monthly dose, so I think having that as an option on the label would be a good route to go. We're also very interested in this potential for off-treatment remission.
This is something that's been a long-standing kind of goal in the psoriasis field. It's defined in the literature as over a year with clear skin after last administration of a therapeutic for psoriasis. We think based on what we've seen with the PK and the potential long-lasting PD effect of IL-23 inhibitors, we could have some percentage of patients going out to maybe a year and a half or two years or more after dosing with clear skin.
We'd love to get that on the label as the first medicine ever in psoriasis to offer off-treatment remission for patients. We think that could be something that really could capture the category as a new way to treat the disease. It's something we'll need more time in the Phase IIs to see how that evolves and how exactly we would bring that in in phase three and get that on the label, but we think it's a very compelling opportunity.
Excellent. How do you see the psoriasis market evolving over the next several years?
Yeah. I think what you see in psoriasis today, BIMZELX and Skyrizi are kind of the category leaders. Both are. I mean, I think Skyrizi is, like, over $20 billion in annual sales now. BIMZELX is now estimated at $8 to 10 billion peak. It's created, like, $35 billion of market cap for UCB. In terms of new molecules in the pipeline, there's really not that much, and we think that's a big strength for Oruka.
If you look at other I&I indications, you have a pipeline that's really full of different mechanisms of action, bispecifics, trispecifics, combinations. You just don't see that in psoriasis, and I think it's logical why. I think IL-23 and IL-17 are the best targets. Now it's about how do we perfect the product profile.
There's a bit of a thinking that orals are kind of the end game in psoriasis, and big investments have been made into those, particularly with the oral peptides and TYK2 inhibitors. I think the goal with that has always been to reach Skyrizi or BIMZELX-like efficacy with an oral, and we just haven't been able to do that. Even the best orals have significantly lower rates of skin clearance than the best biologics.
The value proposition of an oral is really in giving up something on efficacy for a perception of convenience, even though in some cases you require fasting around each administration and that type of thing.
From the discussions that we've had, we think it's not even close in terms of.
We think the vast majority of patients would prefer a once annual or twice annual ten-second sub Q and then forget about the disease for the rest of that period with higher rates of skin clearance than the orals. We think the orals could expand the market.
It's kinda remarkable. I mean, you think biologics and psoriasis have been around for a long time. They're still under-penetrated relative to the number of patients that could benefit from the profiles, and I think orals will capture some of those patients who are maybe, for whatever reason, hesitant to get on a systemic at all and are trying to manage fairly severe disease with topicals, and then that could lead into ultimately biologics being the best option.
We like as we look at this market, which is a $30+ billion market today and growing, we think it evolves in a way that's very conducive to the profiles we could offer.
Excellent. Assuming all goes well, including Part B results next year for ORKA-001, when might you be able to initiate Phase III?
We haven't guided to a specific timeline on that. The way that would go is we've got the Part B that started enrolling December of last year. When that finishes enrolling, then we'd wait for the 16-week primary endpoint from that study. That's the dataset that would allow us to go to the agency and have an end-of-phase meeting and align on a Phase III design and start the Phase III study.
We're getting close. enrollments it sort of depends on how quickly that enrollment goes, and we don't want to be too specific on that. We'll provide guidance on that sometime in the near future, and we are trying to go as fast as possible.
Historically, psoriasis programs have gone through from first in human to BLA in, like, six years. We look at those timelines, and we think we can go faster, and we definitely aspire to. We started our first in human work in the end of 2024, so six years would be 2030, and we think we can probably take some time out of that timeline and get there a bit quicker.
Excellent. Are you thinking about running a head-to-head Phase III trial versus Skyrizi?
Yeah. You don't have to. You can get these approved, running against placebo. I think it's fun to think about going head-to-head against Skyrizi. I think it would take some really compelling Phase III data in order to give us confidence to do that, not something that we would need to do. You could go against a different active comparator, maybe something that would be biosimilar at the time of launch, that kind of thing. We haven't made any decisions on that yet.
Okay. Got it. You meant Phase II. It would take compelling Phase II data-
Yeah.
to do that.
Absolutely.
Okay.
Phase II data. Yeah.
All right. Let's switch to ORKA-002. I guess if you could just start with the BIMZELX adoption being a lot bigger than expected, I think starting there would be helpful.
Yeah. I mean, I think you can see it in UCB's stock price over the past couple of years. I think people underestimated BIMZELX potential and I think that has been a theme that people tend to underestimate what a differentiated biologic can do in markets like these.
I think sometimes they look at the level of differentiation and say, "Well, isn't that incremental?" But those advantages really translate into a very different impact for patients and translate into great adoption. I think UCB reported, like, $2.5 billion in sales in its second year, roughly split 50/50 between psoriatic disease and HS. And that's consistent with the feedback we get from docs that it's found a very important place in the market.
I think it is sort of replacing the IL-17A profile in psoriasis, which tends to be used for people who have concurrent plaque psoriasis and joint involvement or psoriatic arthritis, whereas people with pure skin disease, dermatologists tend to prefer an IL-23. IL-17s work better on the joint aspects of the disease, and so that's where they play the best role.
Obviously, HS is a very interesting market for the IL-17s, and BIMZELX looks like currently the best drug in HS, which is a rapidly kinda growing category as we get new therapies.
Excellent. Could you talk about the target product profile relative to BIMZELX for ORKA-002?
Sure. With ORKA-002, it's slightly different from ORKA-001 in that we're really focused on dose interval advantage. BIMZELX is a new launch. It's branded into the 2040s.
There's really no other IL-17AFs in the clinic other than MoonLake's sonelokimab, which we're aware of. Here we want to be the long-acting IL-17AF. There's really nothing long-acting in the IL-17 class. We think we can get to, based on the half-life that we showed around JP Morgan, which was 75-80 days with that molecule, we think we could potentially get to twice-a-year dosing in psoriasis and quarterly dosing in HS, which would be highly differentiated over anything in the IL-17 class today.
We think it's highly complementary with ORKA-001 in that it's the same kind of physician call point, and a fairly non-overlapping subsegment of a massive market. We'll be starting the psoriasis study first half of this year in HS.
Second half of the year. Very excited about ORKA-002. We think it's probably not given a lot of value in our pipeline right now, which is natural for the focus to be on ORKA-001. We think over time that should represent a tremendously valuable opportunity for Oruka.
Excellent. Could you provide a little bit more color? I know that you haven't provided specific details on those studies, but just high level what you're going to study and what duration?
Yeah. In psoriasis it'll be a pretty straightforward, similar design to other prior biologic studies. 3 different dose levels on that one. We could enable a Phase III start. We'll study 6 monthly maintenance as the primary goal in that study. In HS we're still working through aspects of that design. That one will start in the second half of the year.
We're really trying to look at historically what's been done in different HS studies, what kinda drives placebo response or variability selecting the right dose thinking about geography and how many sizing the trial. With that one we like having HS as a kind of add-on to psoriasis for us. HS.
Psoriasis readouts are some of the most robust, kind of reproducible from Phase II to Phase III. HS is kind of on the other end of the spectrum of it. It can be somewhat unpredictable, depending on kind of various aspects of how you design the study or run the study. We think that we're in a place where we could take our time and get it right.
We want to do everything we do as quickly and efficiently as possible. I think that's one where we may choose geographies where sites have more experience with the studies and the assessment and take a slightly more measured pace to try to get a more predictable result.
I think the BIMZELX results have been very consistent and compelling, so we think we've got a very good chance with ORKA-002 to be a quarterly dosed option in HS would be something really new for patients.
Yeah. Excellent. Let's turn to the sequential combination of ORKA-002 and ORKA-001.
Yeah.
If you could talk about the vision for that?
Yeah. This is a pretty unique, I think creative, strategy that we've gotten a lot of great feedback from docs on. What it's really aiming to do is capitalize on the slightly different profiles of IL-17 and IL-23. IL-17s act fast. They tend to be slightly more potent than the IL-23s, but they come with some sort of nuisance level tolerability effects, the most common being oral candidiasis, which is easily treatable and tends not to recur.
It does cause IL-17s to be used really only for patients that need them, is the way most docs would think about them. They'll use an IL-23 if they think the patient could get a good response. Versus IL-23s are kind of the ideal maintenance regimen. Can act very long long-acting, squeaky clean safety profile.
The idea with ORKA-021 is induce a response with the IL-17, clear the skin fast and potently, and then maintain that response with an ultra long-acting IL-23, kind of the ideal maintenance regimen. It's sort of the best of both worlds is the way we think about it, and we think we're uniquely positioned to do it.
There's really no other company out there that has a great IL-17 and a great IL-23. This is something we're definitely going to run at least a proof of concept study with this and see how the data looks. It's something we could choose to accelerate into pivotal studies as kind of its own labeled regimen. That would depend on, I think, what we're seeing out of ORKA-001 and ORKA-002.
If we get everything we think we could out of ORKA-001, it could be that we just put the afterburners on that one, and ORKA-021 we sort out how it fits in.
Versus if you end up with six-month equal efficacy on ORKA-001, ORKA-021 could be a way to really have a game-changing regimen. So we see it as optionality, another way we could win, another way we could differentiate and have the best biologic regimen in a very important indication space.
Excellent. What have you heard from physicians on their enthusiasm for that framework?
Yeah
It's almost like induction with IL-17 followed by maintenance with IL-23 in terms of that ORKA-021 vision.
Yeah. That's interesting. If you take ORKA-001 to docs I think it's like. Or ORKA-002, it's like 90% are like, immediately get it, you know. I think with ORKA-021, there's more of a split of you'll get folks that say, "That's amazing. I've always wanted to do that. The only reason I don't do that is I couldn't get both reimbursed. Like I've been waiting for somebody to try that." then you'll get a segment that says, "Hmm, like that's quite a bit different from what I'm used to.
I haven't seen something like that. It's not that they're coming up with, I think, a fundamental objection to it, but it feels like the kind of setup where if you had compelling data they could flip and realize that actually this is the way we should be doing it all along.
Yeah.
It is a bit sort of newer concept, a bit unique. It's definitely compelling enough that it gives us a lot of confidence that it could be a very interesting opportunity.
Phenomenal. Well, we are over time, but this has been great. Really appreciate you being here with us today.
Thanks, Dave. Thanks for having us.
All right. Thanks again. Perfect.
Sure.