All right. Go ahead and get started. Good morning, everyone. Tyler Van Buren here, Senior Biotech Analyst at TD Cowen. Thank you very much for jong TD Cowen's 45th Annual Healthcare Conference, Day 2. For our next session, very excited to have a hybrid presentation and Q&A with Oruka Therapeutics. And it's my pleasure to introduce Lawrence Klein, CEO of Oruka. Lawrence, thank you very much for joining me.
Thanks, Tyler.
Go ahead and hand it over to you to do the presentation.
Sounds good. Thanks, everyone, for joining. Good morning. Oruka Therapeutics, we're focused on the goal of advancing the standard of care in psoriatic disease, plaque psoriasis, and psoriatic arthritis, taking one more meaningful step in the product profile of biologics for these conditions. We think it's an extremely exciting opportunity in a very large and well-validated market. We think there's an aspect of this story that is applying de-risked biology in a large and validated market. We're targeting IL-23p19 and IL-17A/F with our co-lead programs. We think you can have a very high degree of confidence that these are the best targets in psoriatic disease.
We think there's an aspect of the story that could really change the treatment paradigm in these indications. We think there's potential to offer patients long-term remissions from their condition, which I'll get into in the presentation. We like this phrase of trying to offer the greatest possible freedom from disease. To us, that means the highest possible rates of disease clearance, together with the fewest number of administrations possible. We are talking about dose intervals of once every six months to once every year, and the potential for multi-year clearance in some people.
We also believe there is combination potential between ORKA-001 and ORKA-00 2 that I will get into. We have some early-stage efforts beyond these. The lion's share of the company's focus is on the co-lead programs. We think that biologics dominate in psoriatic disease and that this is unlikely to change in the near future. A very recent proof point that we think is supportive of this thesis is the way that BIMZELX is launched in its first year, driven really primarily by psoriasis in the U.S. I think countering any narrative around this market being only accessible to the very largest U.S. companies, right?
UCB, Belgian company, doing extremely well in the first year of BIMZELX launch due to its slightly higher efficacy in psoriasis versus the established therapies. I think far outperforming recent oral entry into the field, SOTYKTU , and really showing that what patients and physicians want and respond best to in these markets are new and better biologics. There is clearly momentum in this market to continue rewarding innovation. BIMZELX is a very recent proof point of this.
It is a massive and growing market where, if you look, biologics are still underpenetrated. There are still efforts to go out and bring moderate to severe patients to biologics who have been struggling through with topicals or orals that do not effectively manage the condition. There is still the potential to move biologics into mild to moderate disease where it could lead to long-lasting responses. There is clear evidence that pharma believes in the future of this market. There have been big investments primarily in orals. What we are doing at Oruka is arguing that orals have consistently failed to reach biologic levels of efficacy.
It is really a convenience argument. You are sacrificing efficacy for the idea that people will always prefer a pill. We actually think that most people would prefer a once to twice a year 10-second subcutaneous injection over a daily oral, especially when you factor in things like a meal effect that you run into with oral therapies. We see this in the market research that we have done and that our investors have done.
If you take a base case product profile, this is the minimum of what we think we could achieve, of six-month dosing with equal efficacy to established standard of care, you get numbers like 50% of new patient starts, even projecting forward to what the market will look like in five or six years, which is massive in these indications. I mean, a 10% market share in psoriasis would be a multi-billion dollar product. You can see what BIMZELX is doing. I think it's forecast to $5 billion-$10 billion peak sales now. We are extremely excited to have both ORKA-00 1 and ORKA-002 and the potential to combine them in these indication spaces.
We think it's important to have both a 17 and a 23 and that we are really the only company to have great candidates against these two targets. The way the disease is typically treated is for people with pure skin disease where there's no joint involvement. Dermatologists prefer to use an IL-23p19. It's one of the cleanest mechanisms in all of I&I . If people have joint involvement or they can't reach disease clearance on a p19, that's when IL-17s play the best role. IL-17A/Fs are emerging as the preferred strategy, as you can see with the BIMZELX launch. We think it's a huge strength to have both of these in one pipeline, the potential to offer the best biologic to any person with psoriatic disease.
We think there's a really unique possibility to combine these two sequentially, which I'll get into, that really no one else is positioned to capture. This kind of sums up what we're trying to deliver at Oruka. The core of it is ultra-long dose intervals. We think that is enough to have very valuable products and be immensely successful as a company. We think we can go much further than that. We think there is potential for greater efficacy, which I'll get into, especially with ORKA-001 . We think there is potential to deliver long-term remissions to some patients. I'll show you evidence for that.
We think there is this unique opportunity to combine IL-17 and IL-23 in sequence. What this gives you is sort of multiple ways to win in a massive market, where in the lowest case, we have winners with the ultra-long dosing intervals. In the best case, we could potentially have mega blockbusters products in the portfolio. To just kind of touch on the base case and then these upside levers of differentiation, if you just take the base case of six months' equal efficacy, we've surveyed this quantitatively with dermatologists. We've seen surveys from our investors that they've shared with us that reach similar results.
You get around 50% of new patient starts and 30% of switches, even projecting forward to a market where JNJ-2113 is approved and things have advanced from today. Those are incredibly compelling numbers just for the base case product profile. We think there's great evidence out there that dose interval is a real differentiator. You really don't need to look any further than SKYRIZI versus TREMFYA in psoriasis, where SKYRIZI's dose is once every three months. TREMFYA's dose is once every two months. They're viewed as having similar efficacy.
If you ask dermatologists why SKYRIZI is used so much more frequently, they'll say, "Well, I offer the once every three-month version or the once every two-month version. And what would you choose if you had the condition?" It's not that hard to understand. We think we can go further than that. There's evidence that dosing IL-23 inhibitors higher can lead to higher levels of efficacy. There's great evidence support for the safety and tolerability of higher doses. This is an investigator-sponsored trial called KNOCKOUT. It's run by Andy Blauvelt, who chairs our scientific advisory board.
He dosed SKYRIZI at 2x-4x the approved dose, so 300 mg-600 mg in 20 patients. He saw 20-30 percentage points higher PASI 100 than was seen in the SKYRIZI phase III, which is pretty remarkable. SKYRIZI averages around 43% at 16 weeks. He saw 67%. Now, all appropriate caveats of this being a small cohort and investigator-sponsored work. It fits a broader trend. If you look at the phase III, twos, and threes of SKYRIZI, you also see this behavior with TREMFYA, where as you increase in exposure across patients, if you sort of separate them into exposure deciles, you see an increasing PASI 100 rate.
Basically, what we're asking you to believe is if we take these gray dots and shift them all over to the right-hand side of this axis, are we likely to see higher PASI 100? We think that's a very strong case to be made. Again, we don't need this to have successful products here, but it would be a multiplier, we think, on their value. It is quite likely to emerge from our studies. If you put this together and you say, "Well, what if we dosed ORKA-001 with a 75-day half-life, which is sort of the mid-range of what we might expect to see from our phase I study based on our 30-33-day NHP half-life? What if we did a single dose of this?"
This might be two autoinjectors, but for once a year, that's very manageable. We would get this exposure shown in blue. Again, this is modeling. We'll need to see the real data from our phase I, but we think this is quite likely. This in orange dotted is what the average patient would have seen on the KNOCKOUT study. Basically, what we're saying here is we might be able to achieve what was done in KNOCKOUT with three high doses with a single annual administration and keep levels of antibody above the trough level needed to maintain response for the entirety of a year. We could have a once yearly therapy that delivers greater efficacy.
We think that would be viewed as game-changing in a $40 billion market. We think some people might go longer than a year. There's evidence that IL-23 inhibitors deplete tissue-resident memory cells from the skin and that this leads to long-term responses. The median patient, if you take them off SKYRIZI, stays in clearance for nine months, even though it's dosed every three months. We think for an incumbent in the market, it's very challenging to really unlock an opportunity like this, but we could.
It is something that we absolutely want to test in development. I will show you how we are doing that. We think it could be a huge differentiator for us. One final kind of axis of additional differentiation is this sequential combination. IL-17 inhibitors have faster skin clearance, and they clear a higher percentage of people, so they are a bit more potent. They do come with some nuisance safety events like oral candidiasis that IL-23 inhibitors do not have.
All things being equal, dermatologists would prefer to have patients on an IL-23. What we could do, because we are really the only company with both a 17 and a 23, is dose IL-17A/F in induction, so ORKA-002 in induction, and then transition to ORKA-002 to keep people clear. It could really be a best of both worlds. The feedback we have gotten has been really strong. We view this as another way to win in this market. We want to have the best biologic regimen in psoriasis. We think there's multiple different ways that could emerge from our development plan. I'll get to that. We're in the clinic now.
We started our phase I study with ORKA-001 in December of last year. It's a single ascending dose escalation study that will allow us to read out the half-life of the molecule in humans, which is a very important de-risking point for these programs. We're going to rapidly progress into a phase II in psoriasis, which we're really excited about this phase II- A design. This will start later this year. It's a very innovative design, around 80 patients planned in moderate to severe disease. They'll all receive ORKA-001 . There will be a small placebo arm that crosses over quickly.
The primary endpoint of PASI 100. PASI 100 has never been used as a primary endpoint in a psoriasis study. We are excited to push the boundary there of what has been done. It is a primary endpoint at week 16 where we could test this hypothesis of higher exposures leading to higher efficacy. At a midpoint here, we are going to randomize people into a maintenance arm where they receive twice a year dosing, which is sort of our base case profile. We want to lock that in. We are going to have a cohort of people who are not redosed until disease recurrence.
If you can imagine what this is going to allow us to do, it is essentially capture the Kaplan-Meier curve of how long responses last after last treatment. It'll allow us to determine do we have a year efficacy, a year duration in a very high percentage of patients. This will be open label, and we'll follow these patients for quite some time. This will allow us to potentially say something like 20% of patients go two years or longer with clear skin after their starter doses. That's something we imagine ultimately having the chance to get on a label and really be the first biologic to show remissive-type efficacy in this indication, which we think could shift the treatment paradigm.
We're moving fast. In the clinic now, and we have a cadence here where we'll have an important clinical catalyst every six months for the foreseeable future. We've got second half of this year. We'll read out PK from this phase I study of ORKA-00 1. We're planning to be in the clinic with ORKA-00 2 third quarter of this year and read out PK in the first half of next year. By the second half of next year, we'll have data on this phase II-A study. Psoriasis data has been very robust from phase to phase. Challenge you to find a psoriasis study that did well in phase II and then didn't in phase III . It's very reproducible.
The placebo rate for PASI 100 ranges from 0%-0.8% across dozens of studies. It's a very robust endpoint where we think de-risking at phase II-A will read through to the future very nicely. Importantly, in these markets today, we're very well funded. We have cash through 2027, which gets us through all three of these clinical readouts, plus more than a year of runway beyond that. That is my last slide. I will end there and take questions.
Perfect. Thanks very much for that presentation, Lawrence. Did a great job. Cut the time precisely down the middle. Q&A. Let's start with 001 and the update that we're going to get from the phase I trial. I think the target 75-day half-life. If you achieve that or better, what's your level of confidence in being able to dose it once every 12 months or once a year?
Yeah. We had 30 days- 33 days in non-human primate. There have been a lot of YTE antibodies now that have gone from NHP to human. The range is around a 2x-4x from NHP to human. That would be 60 days-120 days, with 90 being around the midpoint of that range. The way we've really tried to message this is we need 50number to get to six months. 75 makes a year possible for everybody. I think if we had 75, there's going to be a very sizable percentage of patients who get to once a year with clear skin. Is it going to be 100% of patients? We'll have to test that in the phase II. Again, it doesn't need to be. We could imagine a label that has both six-month or one-year options on it.
We think we're very likely to be there.
Got it. Other than safety and exposure data, will there be other biomarker data from that phase I that we could look forward to?
We will look at some PD markers. At the same time, we think really the PK is going to be the key piece of data. If you have IL-23 antibody in the serum, you can be pretty confident that you're going to affect the disease, and a biomarker is not going to add a lot to the understanding of that.
Got it. You spent a good amount of time on the KNOCKOUT trial of high-dose SKYRIZI. In the phase II, you mentioned that you have the placebo patients going to 001, and then they're not being treated until disease recurrence, so almost like a treat and extend to see how far you can extend them. Maybe you could elaborate on the recent two-year data for the KNOCKOUT trial and what you saw there as we think about what that arm might do in the phase II.
Yeah, absolutely. We think it's very compelling in KNOCKOUT. Around 10% of people made it to two years with clear skin. That's with a much shorter half-life than we anticipate having here. We think it's very likely that we'll have a higher percentage of patients clear at two years. Something like 20% of patients clear at two years after starter doses is absolutely in the realm of possibility. Here, it's actually really well supported by clinical data. We think that's a huge differentiator that we could have with ORKA-001 .
Let's say you achieve a very exciting result, like 20% of patients controlled after two years. Is that something that you could incorporate into your phase III, or is that just more of a commercial consideration?
We absolutely could incorporate that. I mean, what we would imagine doing is you could imagine a protocol that says, do induction and then do not redose until disease recurrence. If disease recurs, initiate a once every six months or once every year maintenance regimen. That is how we envision this might be ultimately used. We could study it that way in phase III , which would give us good data to think about how we would commercialize that.
It would likely be an additional arm, right? You'd have multiple arms with like a fixed and then a kind of treat and extend.
Correct. We could do that with a portion of the patients.
Okay. In the phase II-A trial, I mean, as you mentioned, if you have once or twice a year dosing in this market and you get a good portion of it, that's a multi-billion dollar drug with similar efficacy and safety. Just in the phase II-A trial, what's the optimistic goal on the PASI 100 given the KNOCKOUT data?
Yeah. SKYRIZI averages around 43% at week 16 in the phase III's. Varies a bit from study to study, but pretty tight range. KNOCKOUT was 67%. Of course, we would be very excited to see KNOCKOUT levels. Again, we do not think we need any advantage on efficacy. Any upside on efficacy beyond standard SKYRIZI, we think would be icing on the cake here. We think it is very possible given what KNOCKOUT showed.
Yep. Let's move to 002, IL-17. How are the startup activities going for the phase I trial? When should we expect first patient treated? I guess that data is coming first half of next year, right?
Yeah. Guidance is third quarter of this year, and everything's on track. We're, of course, a team who tries to take every possible day out of the timeline that we can. We're really laser-focused on rapid and efficient, high-quality execution. We're going to move things as fast as we can. That's the guidance. Yeah, that would lead to likely the PK data being first half of next year.
How do you think about as you think about the combination of 002 and 001, how do you think about the safety considerations with BIMZELX ? Do you think that would likely carry over with your product, or will it be different if you just use it in induction versus chronic dosing?
Yeah. We think that's one of the appeals of ORKA-21 is there are some, I characterize them as nuisance safety events with BIMZELX that lead people to prefer to use a 23 if they could. We would think that if you just dose the 17 in induction, maybe you have those events for a short period of time. That's a very different proposition than those continuing on and transitioning to an IL-23 in maintenance could be sufficient to keep people clear and offer that very, very clean safety profile of a p19.
In general, as we think about 002 monotherapy, do you think that it's going to be a class label with BIMZELX, or do you think that the FDA is going to take into consideration what you all observe in your trials?
Yeah. I mean, the primary safety event is oral candidiasis. And it occurs with all 17s. It occurs with 17As as well. It is higher frequency with 17A/F. We do see some evidence that more infrequent dosing, if you look across studies, could lead to lower rates of candidiasis. I think it is going to be determined by what rate we would see in development, how that looks. It is something that is across the class. It is not a significant event, but it is a nuisance that steers people towards a 23 if they can manage on a p 19 inhibitor.
Got it. The ultimate goal, if everything works out, is to have 001, 002, and 21 as three different options to offer to patients.
Yeah. I think if we get everything we want to see out of ORKA-001 and ORKA-00 2, there may not be a reason to pursue 21 aggressively. We see it as another way to win. We want to have the best biologics in this indication space. Some of this will be exactly how we put the emphasis on one or the other will depend on the data we see and how the field emerges. We think this creates maximum optionality for us to have that best biologic regimen.
Okay. Taking a quick step back with ORKA-002 and the phase I readout in the first half of next year, what should expectations on half-life and dosing for that readout be?
Right. We'll read out the half-life from the phase I, and that'll give us a sense of what to expect. In the phase II- A, that's the design. It's going to be that design independent of what half-life we achieve. That's just going to sort of change our expectations on what we'll see. By the second half of next year, we'll have that 16-week endpoint for everybody. We'll have some patients that are out to a year or longer at that point where we can start to see what that Kaplan-Meier curve looks like. Of course, it'll take longer for that to fully mature. We'll be able to say something about response duration second half of next year.
Okay. For 002 for half-life, what expectations are you doing?
Oh, I'm sorry. You're asking 002. Yeah. 002, we'll have preclinical data in NHPs out soon. We think with that one, we can get to two to three times a year dosing, so once every six months or once every four months. When we put out the preclinical data, we'll talk about what half-life is required to achieve those. We think it's well within the range of what we might see.
Okay. What are your latest thoughts on indications beyond psoriasis? Obviously, UCB and Novartis have been pretty bullish on HS lately. Curious to get your thoughts there.
Yeah. We're excited about what's happening in HS and the potential size of that market and the fact that BIMZELX looks like the best drug. And we could have a longer-acting 17A/F in that indication as well. We're laser-focused on psoriasis and psoriatic arthritis as a first place to go with these because we think we can have differentiation in a massive, well-validated market. But 17A/F has a number of indications beyond PSO and that are interesting: HS, ankylosing spondylitis, PPP, uveitis. So we're looking at a number of those for expansion. I think HS is probably the top of that list. But it would come after PSO and PsA for us.
Okay. When might you guys be able to start clinical activities in PsA?
That'll come soon after PSO. We'll plan to run those phase IIs in parallel.
Okay. Given all the talk on KNOCKOUT and the improved PASI 100 rates with the higher doses, do you see a dose exposure response with BIMZELX or IL-17? Is there an opportunity to take the induction up higher with ORKA- 002?
Yeah. We've picked out a part we don't see as strong of an exposure response with 17A/F as we do with IL-23. The opportunity is not as clear. We think that actually is encouraging in the sense that IL-23 really stands out as having a clear opportunity there. We will plan to test some different doses in phase II with ORKA-00 2. We wouldn't rule out the possibility of greater efficacy, but it's not as clear a case as with the 23.
Okay. What's the latest on cash runway?
Yeah. We have cash through 2027. Again, that gives us over a year of runway beyond those three clinical catalysts, including the phase II data for ORKA-00 1.
Wonderful. With that, to wrap up, I'd like to ask you what you believe is the most underappreciated aspect of the story, the Oruka story by investors.
Yeah. I think at the surface level, people may think of Oruka as de-risk biology, incremental improvement in a large market. We think that is a piece of the story. It is a compelling piece because if you can have a large opportunity while taking minimal biological risk, that's a great investment case. At the same time, we think there's an angle of this and an opportunity that's really paradigm-changing in a disease that affects 8 million people in the U.S. alone. We think we could offer long-term remissive-like efficacy. We think this is the closest you could get to a cure in this indication in the foreseeable future. We're extremely excited about offering that for patients.
Wonderful. With that, I thank you for your time, Lawrence.
Thanks, Tyler.