Very happy to have Oruka Therapeutics CEO Lawrence Klein with us this afternoon to talk about the story. Maybe I'll kick it over to Lawrence for a brief overview of the company, and then we'll get into a Q&A. Lawrence, over to you.
Sure. Thanks, Alex, and thanks to everyone for joining this afternoon. Oruka Therapeutics, we're focused on advancing the standard of care in psoriatic disease, and our pipeline is anchored around two co-lead programs, which we call ORKA-001 and ORKA-002, which are ultra-long-acting antibodies targeting what we believe are the two best targets in psoriatic disease, IL-23p19 and IL-17A/F. Both of these antibodies are now in phase II studies. We've read out phase II data from two independent phase II studies with ORKA-001 up to week 28 or month six, showing what really are, we think, best in indication efficacy figures, clearing the skin in moderate to severe patients at a rate of over 60% in both independent studies, which is very exciting. With the potential for dosing potentially once annually, with a six-month option, which is our intended TPP for that program.
There's never been a once-annual-dosed medication in any chronic immune disease, so we think that could capture the imagination in a new way and really be impactful for patients. We've got an important readout in December coming up that will help to elucidate just how well we maintain responses out to one year, and I'm sure we'll get into kind of the details around that readout. But what we like about our setup is that is intended to go into phase III in the first half of next year, and that's a big activity within the company right now, is preparing for that. But beyond that, we've got a nice kind of sequence of potential catalysts to grow our pipeline beyond ORKA-001. We're aiming to have psoriasis data for our ORKA-002 17A/F BIMZELX-like molecule in the first quarter of next year.
That molecule's also in an HS study, which is enrolling well. We haven't set a timeline on data yet, but that'll probably be the next data event. Beyond that, we have a third program, ORKA-004, which is an extended half-life TL1A, which we want to use in combination with both one and two. We think a combination of ORKA-002 plus ORKA-004 in HS, so a TL1A IL-17A/F combo in HS could be a very interesting way to potentially break through an efficacy ceiling in that disease, and maybe branch out even further with combinations beyond that. So lots of ambitious plans at Oruka and exciting things going on.
Great. Maybe I wanted to start thinking about psoriasis in particular. Psoriasis is the market where everyone points to a market that's been solved in the progression of dosing, et cetera, and how that's driven opportunity among some of these new next-gen agents. What kind of is the remaining unmet need in psoriasis that you're going after at this point?
Yeah, it's interesting. There's been a progression in the standard of care for psoriasis over the past maybe 30, 40 years from where we started with really broad immunosuppressive agents, steroids, and things of that nature, to targeted agents that address a very specific aspect of the immune system. It's interesting to talk to dermatologists who've been in the field through that whole trajectory. Some of them would say, when we first saw STELARA, which is an IL-23p40 antibody, they said, "Isn't this disease solved now? That's as good as it gets, right?" Then TREMFYA and SKYRIZI came along, and SKYRIZI is now on track to, I think, be the second-biggest drug in all of biopharma, second only to tirzepatide, because it clears the skin for a higher percentage of people and is dosed very infrequently and has a very, very clean safety profile.
Now people are trying to push that further by applying that same target, IL-23p19, in an oral format, so getting to an orally available agent that inhibits that same cytokine. What we've run into there is, you end up with lower efficacy, and you still have to take a pill every day. What we've done at Oruka is we believe that actually maybe the ideal product profile, maybe really to solve this disease in a way that it really becomes hard to improve on, could be something as infrequently dosed as annual with very, very high rates of skin clearance. That's what we've started to show with ORKA-001, and we think we can further elucidate. We think this could be the end game in psoriasis.
We think it is a little hard to imagine what comes along beyond this, because I think these are clearly the two best targets in the disease. But yeah, we think there's still meaningful advancement.
Can you talk about the fundamental kind of biological insight around getting to that 60%+ PASI 100 rates that you are seeing across two trials relative to the 40%-50% from SKYRIZI?
Yeah, a large component of that is exposure and response. It is really pretty simple, is how much antibody is in the bloodstream correlates with how strong the response is. The first IL-23 agents, it is very clear if you go back and look at how they were developed, they were not dose-optimized . One very clear point of evidence is they are dosed much higher in IBD, and they were developed later in IBD. If you look at the way the psoriasis doses were originally selected, a lot of it had to do with how much could fit in an auto-injector at the time and the formulations that they had at the time, which were not quite what we are able to do today. They were not fully dose-optimized.
They ended up using a higher dose in IBD to get higher efficacy, and then more data came out that suggested that if you went to higher exposures, you could potentially drive higher responses. That is what we picked up. We picked up that thread with ORKA-001, tested it at significantly higher doses than the approved IL-23s, and we saw those same very high response rates, close to 20 percentage points higher than other IL-23s at week 16, which is pretty remarkable.
Yeah, maybe let us talk about the designs of EVERLAST-A and EVERLAST-B, and basically the data that you have seen across both those studies at induction so far.
Yeah, those are randomized placebo-controlled studies, two independent studies in very different site footprints, so really very independent tests. One was a single dose level. EVERLAST-A was our 600 mg dose, which was what we always thought would be our go-forward dose. EVERLAST-B is dose- ranging, so it included three different dose levels. It was intended to satisfy a requirement that regulatory authorities like to see dose-ranging studies to justify a phase III dose. Both of those showed very similar efficacy at the 600 mg dose of low 60s PASI 100, mid 80s PASI 90. I think it's interesting that that's very similar efficacy to the best in indication efficacy so far seen with BIMZELX.
Yeah.
Which I think indicates that that may be a maximum efficacy of inhibiting the IL-23/IL-17 axis. I don't think it's a coincidence that we saw very similar efficacy to BIMZELX in both of those studies. But it's remarkable. I mean, to have that in the format of an IL-23p19 that could potentially be dosed this infrequently, if you take that out and survey that with docs, you'll get pretty incredible potential market share numbers.
You basically saw that replication in week 16 for the 2a. We've now seen week 28 data, and then after week 28, we've now randomized patients to either no dose until recurrence and then six-monthly dosing, correct?
Correct.
This next update in December, we're going to get this 52-week data. How would you paint what you want to see out of this 52-week dataset?
Yeah, so this will be the first direct test to say, can this be an annually dosed regimen? To really show that, you've got to dose people and then wait a year.
Yeah.
There's really no shortcut to showing. We've got PK that suggests the potential for good maintenance at 52 weeks, because we've shown that the drug should still be around in the bloodstream at levels that could inhibit signaling. But to really directly test that, you've got to follow up for a year. And in December, we'll have that whole EVERLAST-A cohort out to one year s ince they started in the study.
There's a group in that study who were all clear at week 28, so around six months, and they do not receive any additional dosing beyond their induction dosing at the start of the study. They will be a year out from last administration of any therapeutic for their psoriasis. The question will be, how well are responses maintained? We are going to show a holistic picture of the data at week 52 in December, where you get a sense for the overall maintenance. If there's one number that I think people will focus on, it will be the percentage of those people that have maintained PASI 100.
Sure.
All the way out to week 52. There's good benchmark data for this, but we've sort of been pretty clear that the window we see for being excited about once-yearly dosing with this molecule is anywhere from 50%-80% maintenance. 80% is kind of the maximum you could hope for, because that's what a frequently dosed regimen would see on this metric. You are never going to get 100% because of the way the disease can fluctuate.
Sure.
If you are over 50%, you've got over half people maintained at a very strict high bar, PASI 100 at week 52. That would be fantastic to see. I think, of course, we'd like to see it towards the upper end of that range.
Sure.
But anywhere in there, we think we've got a very exciting first-ever once-a-year product candidate for a big market.
I guess the upper end of that spectrum, 80%, comes from the UltIMMa-1, UltIMMa-2 pivotal studies for SKYRIZI. As you alluded to with your phase I data, you maintain trough coverage above SKYRIZI at one year, and that's just one dose versus the induction protocol that you had in the phase IIa. I guess based on everything that we understand about these cytokine-targeted antibody approaches, why is maintaining trough coverage not going to get you to the same outcome?
Yeah. So if you just look at the PK, you can start to get pretty confident that maintenance at a year should look pretty good.
Yeah.
Because the PK is very strong, and you should have drug levels around at a significant level. I think it's important to keep in mind a couple of things. One is PASI 100 is a very stringent bar.
Sure.
People come into the study with a PASI of like 20. That could be your entire torso covered in a thick psoriasis plaque. They get all the way to zero. That means no detectable psoriasis anywhere on the body surface. A physician couldn't diagnose psoriasis in that patient if they didn't know they had the disease. You could have disease come back to a score of a 0.2. Person might not even realize that that's happened.
Could be a tiny little patch on the back of their arm, but the physician sees a little scaling, and so scores it as zero. That person's not a PASI 100. That person probably has no interest in being redosed for their psoriasis, probably very happy with the outcome with a one-year regimen, yet they don't show up as a PASI 100. One is, important to remember how stringent that bar is. The second is, this is uncharted territory. We've never seen a once-a-year drug for any chronic immune disease. There could be, for instance, psychological factors.
Sure.
You are a year out since the last time you got a dose for psoriasis. You have been clear for nine months. Maybe you start doing some of the things in your life that you knew could make your psoriasis worse because you feel like you have been cured of the disease. Could that make a few more people come back to a 0.2 or a 0.4? I think it absolutely could. I do not think we should get overconfident with the PK. I think the PK is very supportive, but I think there are two important things to keep in mind, that it is uncharted territory, it is a very stringent bar. If we get 60% maintenance and the rest of the people are at a very low recurrence where it could just be natural fluctuation of the disease, that is a fantastic profile.
How should we think about the other arm, the six-monthly arm here, and how should we think about those data relative to the no-dose dataset?
Yeah, I think the six-month arm, you can have more confidence because it is less uncharted of—
Sure
—you're getting a second dose, you've got another peak of Cmax that could contribute to keeping the disease at bay. The overall exposures are higher. Our expectation for that arm is it should look at least as good as maintenance with these other regimens. It does seem like this 80% number is pretty consistent across different regimens, like SKYRIZI, TREMFYA, even frequently dosed orals. They all kind of come in around 80%. What we think is happening there is you start out with a group where everybody's clear, you get some natural fluctuation of the disease. It's not necessarily that the disease is coming back towards baseline. It could be somebody who's at a zero one visit, shows up as a 0.2 the next visit, and then they're back in a zero—
Yep.
—some amount of time later. We've set a strict bar for ourselves, a very high bar with PASI 100. I think we've cleared it now in multiple studies. I think it's worked in our favor. I think we're going to see really good maintenance here based on the PK, but we'll just have to see how things play out.
Then maybe over the longer term, one of the other questions around exposure here is the impact on these resident memory cells. Are you expecting to share any of those data in this study, and sort of how are you thinking about disclosure beyond this one-year period over time?
Yeah, we're turning around this data, or our plan for December is turn it around pretty quickly. The study finished enrolling last December, so you can imagine week 52 visits are one year later. We've got visits in December. We've got to have those visits to get all the data, then clean all the data, and get it ready to present. The TRM data comes from biopsies.
Yep.
You're going to collect those biopsies, but then they've got to go through a whole pipeline of analysis that's actually done at an academic site, so it takes a little bit longer. That data will probably take a little longer to get access to. We're really interested in it. We think it could provide evidence of disease-modifying effect that could lead to potentially even longer-lasting responses in some people beyond the one-year mark. I think that's a nice thing about the EVERLAST study is beyond December, it could be a gift that keeps on giving for us. I think data at two years or three years could be really interesting if you have some people that are maintaining a sort of remittive-like effect. I think that could just add to the enthusiasm around this profile, which is already quite high.
Same sort of idea for EVERLAST-B, what does the long-term data look like there?
Yeah, similar study there. You have a no-dose arm where we can follow up, similar to what we are doing in EVERLAST-A. There is not as much dosing at six months, so there we let more people go through to the one-year mark so we can get more evidence for annual dosing. It will just add to the overall picture in advance of having a mature phase III dataset.
You have alluded to starting a phase III next year. What is the path for that?
Yeah, the key step is an end-of-phase meeting. It was really the week 16 data from EVERLAST-B that we needed to have. That was the data we put out just a few weeks ago. We're gearing up to have those discussions. We think that that dataset couldn't have come in any better for us in terms of potentially getting alignment on our desired dose level.
We've got all our designs set up, and the teams worked really hard, and I have to give a tremendous amount of credit to our team on the type of progress we've been able to make and how thoughtful they are on thinking ahead and making sure that things like all the CMC requirements, all the operational requirements to get sites open, and IRB submissions approved, so that nothing else would be gating on a phase III start, and we can get going as quickly as possible.
Should we expect to see an active comparator in your phase III?
Yeah, I mean, most psoriasis phase IIIs for biologics have had an active comparator. Most physicians would expect to see an active comparator and might view a study that is simply placebo-controlled a little bit differently. We do want to have an active comparator. I think we have tried to manage expectations that it is probably not going to be an IL-23p19.
Is Stelara the obvious one?
I think there is a lot of logic to that, given that is the one that would be biosimilar on the timeline that we would plan to launch. There is no requirement to have an active comparator, and I think people overestimate the impact it actually has with payers. I think it actually does not really change the dynamic all that much, but I think that could make sense as a selection for an active comparator.
Okay. Let's pivot to ORKA-002. I guess maybe at a high level, how are you thinking about ORKA-002 and ORKA-001 fitting together in your pipeline?
Yeah, sometimes we get the question of, based on the fantastic efficacy we've seen with ORKA-001, do you still see a place for ORKA-002 in psoriatic disease? We unequivocally, 100% see a huge opportunity for ORKA-002 in psoriatic disease, and then also in HS. I think you just need to look at BIMZELX and what it's doing for UCB. They were a $10 billion market cap company when they launched BIMZELX. I think now they're like $60 billion. I think peak expectations on BIMZELX are getting close to double-digit billions and probably get there. It's doing incredibly well. It's doing incredibly well in psoriatic disease. It's doing very, very well in HS. There's other indication potential.
The reason it fits really nicely with the ORKA-001 in psoriatic disease is there are different patient subset segments, and it's really 17s work better for people with concurrent psoriatic arthritis, so joint involvement. Which is 25 or so percent of people with moderate psoriasis, and given how big these markets are, that's a huge segment. If you just have an IL-23, you're missing the opportunity to potentially serve patients who have both PSO and PsA. They fit really nicely because it's the same call point, it's the same commercialization infrastructure. We see them as very, very complementary in psoriatic disease, the potential to have the best biologic for any patient with a psoriatic condition. I think that's incredibly powerful. Then obviously HS. I think there's been a lot of data in the last three months or so on HS. It's been action-packed.
Yeah.
Very dynamic. I think BIMZELX emerges from all of that as pretty clearly still the best mechanism. I think TL1A is maybe showing some interesting signs of being a challenger, but it's early. We've just seen one phase II. I think we've seen some other mechanisms maybe not show as interesting data. I think that sets us up to potentially have some really compelling opportunities in HS, which I think is a very natural next step for us beyond psoriasis.
You're going to have your first phase II readout in psoriasis in the first quarter of next year. What should we expect in terms of efficacy there relative to BIMZELX in psoriasis?
Yeah, BIMZELX-like, on both efficacy and safety. We've been very clear on this one. With the IL-23, there was all this data to kind of point us in the direction of higher exposures, maybe higher responses, and then we showed that. I think with 17AF, there's not that same data. We're not sandbagging when we say—
Yeah.
—should be similar efficacy. We don't see any data to suggest we could have better efficacy. It looks like BIMZELX is sort of maxing out.
Yep.
I think it fits with that picture of that being kind of the maximum you can achieve with that pathway, with the IL-23/IL-17 axis . So, similar efficacy, similar tolerability. If there are little variations numerically in either direction, we'll be the first to say that's probably some cross-study effect. It'll revert to the mean in a larger study. The molecule has a very similar epitope, both cytokines, very similar affinity. We're studying it at very similar exposures. I think our ingoing expectation should be it should have a very similar profile with the potential for dramatically extended dosing.
Based on the phase I data you have so far, what are you expecting in terms of dose frequency relative to BIMZELX in psoriasis?
Yeah, we think we could be once every six months in psoriasis and quarterly in HS, whereas BIMZELX is once a month to once every two months in psoriasis and once every month in HS. The induction regimen we think can be a lot less burdensome, where they do very frequent induction dosing. We think we can get by with just a few induction doses.
Then, going back to the phase II study in psoriasis, totally makes sense on the question around efficacy looking similar within reason. On safety particularly, I think candidiasis is the one adverse event folks probably will be focused on. Are you worried at all that looking for this or being aware of this as an adverse event sort of might increase the rate that it's found? How are you sort of thinking about that?
Yeah, I think one can expect that once you know an event is likely to occur with a mechanism, you might pick up more of those events. I think I'd say a couple things. One is the IL-17 profile overall is very, very strong tolerability. Candidiasis is at most a nuisance event, very easily treated, resolves, tends to not recur. That's a very important feature. It's not like these people are commonly getting recurrent candidiasis. You tend to get one event and it doesn't recur. I don't know. I think ingoing expectations should we see similar rates. BIMZELX rates do vary from study to study. I think we all saw that kind of trajectory with Apogee where there was a reaction—
Sure.
—where the first conjunctivitis rate came in a little higher and then it ends up reverting to the mean in a broader study and after more time. Either way it goes, if we have lower rate of candidiasis, I will be the first to say we probably end up with something similar to Bimmy at the end of the day. If it is a little higher, I would encourage people to see it the same way.
Yep. The other element of the BIMZELX label, which obviously may not be something that you would see in phase II, is the warning around suicidal ideation behavior. This gets back to kind of this question around, like, is infrequent dosing always better? How are you thinking about that as a safety question for ORKA-002, and sort of how are you thinking about that overall?
Yeah, that one we do not really hear much about anymore.
Yeah.
To be honest. I think when we started the program a few years ago, you definitely heard a little more because of the whole experience with brodalumab. I think it is generally accepted to have been a spurious finding.
Yeah.
When it did show up, it was driven by like a single event—
Yeah.
—in a pretty big study, and then it has not shown up again. It is always a scary thing to think about, and you got to take it seriously, but I think at this point, it is not a concern for physicians with this mechanism.
You alluded to, obviously a lot going on in the HS space. How are you thinking about running an HS study that sort of accurately reflects the efficacy of ORKA-002?
Yeah. There's definitely been a trend towards higher rates of placebo response in HS over time. You can see that in the data. I would say there's also a trend towards the less potent the mechanism is the higher the placebo rate tends to be.
You can see that even going back a ways. When you have mechanisms that have failed to show efficacy, you end up with a higher placebo rate. I think there's some reasons why you could imagine that in a placebo-controlled study. But even setting that aside, there is a sort of uptick, and that could be because you're getting more subjects into the funnel because there's more disease awareness, and so maybe you're getting people whose disease is going to naturally fluctuate a little more because they haven't had it as long or various reasons. We've tried to control for it. We don't have a silver bullet. I think we have a few things going for us is, we have one of the most active mechanisms in HS. We know that with IL-17A/F. It's shown good data in HS numerous times. We've chosen a pretty narrow site footprint.
We think that could matter. We're North America only, and we're testing only one dose level, and we did that consciously because we thought if we split a population across a number of doses, given how much HS data fluctuates, you're more likely to be misled than learn anything meaningful, and that allows you to power the study up more where even if you do see a higher rate of placebo, you're still likely to have a positive outcome. I would say there's more inherent risk in an HS study than psoriasis, and that's part of the reason we started in psoriasis first, so we can validate the mechanism there, so there's a little more kind of cushion. Then it's sort of a next indication for us, so it's not the core of our thesis.
Sure.
I think it's a great way to sequence things, and we're very optimistic that we can show good data.
Should we expect to see data next year?
We haven't said yet. We want to see that one, we've been clear. Psoriasis, we've really tried to put the pedal to the metal and go as fast as we can. On HS, it is a balance, we think, between going fast and choosing great sites and being real selective in how you're running things, so it may enroll at a little more measured pace. It's off to a good start, and we'll probably set guidance on data sometime in the near future.
Yeah.
We haven't said when that would be.
So then, obviously, we talked about psoriatic disease broadly, but we haven't yet talked about psoriatic arthritis. So, where are you thinking that fits into the clinical development landscape across even ORKA-001 and ORKA-002 as well?
Yeah, so both ORKA-001 and ORKA-002 should be active in PsA. We eventually want to seek a PsA label. That means running a phase III study for both of those in PsA. The question is just when.
Yeah.
And that's really a resource allocation question. If we had unlimited resources, we'd probably start those right away.
Yeah.
But you don't need to. You get a lot of usage in PsA if you get a PSO label because those two go together.
Yeah.
There would be an understanding that these mechanisms are active. Existing successful products have often gotten the PsA label added one to three years after the psoriasis indication. That is something we are evaluating, not if, but when is the right time to start those studies.
Then maybe lastly, turning to ORKA-004, where do you see the most obvious sort of application of TL1A towards your pipeline? Is it definitely HS, or are you thinking about other strategies as well?
Yeah, other strategies as well. I would say right now, top of the list is TL1A plus IL-17A/F and HS. I think based on what we have seen in the past few months, that very clearly bubbles to the top as the most exciting potential combination regimen, and really maybe the only near-term opportunity to kind of break through the efficacy ceiling we have seen with monotherapy mechanisms. I think it is hard at this point to imagine a monotherapy mechanism that is going to do meaningfully better than 17A/F. I think that combination really could, and that we could maybe be the first with a proprietary combo.
With that strategy, and that's pretty exciting. We want to prioritize that. We started the TL1A a while back with the idea that it could be important in a lot of these disease areas. We originally thought maybe it'll be important in psoriatic disease, where combinations with IL-23 or I think Spyre's data being negative in PsA teaches the field a lot. I think it was somewhat unexpected, but that lowers a bit in terms of our relative priority. I'd say HS is first and then ideas beyond that, but we could benefit from seeing additional data. That's a mechanism that's being tested in a lot of different indications by a lot of different companies right now, so I think we'll learn a lot more.
When might this get into the clinic?
We said next year. We said we want to start a combo study. Oh, sorry. It'll start phase I around the end of the year.
Okay.
That is getting really close. Then we have said we want to start a combo study with the TL1A next year, and HS is our top candidate for that—
Okay.
—right now.
Maybe cash runway and what is embedded in those assumptions?
Yeah, $1.2 billion as of our Q3 earnings, which was recent, so really strong cash position. That gets us, we have said, through BLA for ORKA-001, so that is fantastic to be able to say. That is a really robust plan that includes registrational studies for ORKA-002, that includes the combo work that we talked about. It includes a lot. If we end up doing all of this in every indication we could imagine, there is probably more required, but we are in a really strong position at the moment.
Awesome, Lawrence. Well, always a pleasure. Thank you.
Thanks a lot, Alex.