Featured company, Incyte, represented by their chief medical officer, Steven Stein. Thanks so much for joining us, Steven.
Thanks for having me. It's good to be here.
A lot to cover. I don't wanna spend the whole time on 989 because I know you have just a few other things in your pipeline. I do wanna start there just because I know it's a topic of high interest, and there's a lot of recent data and developments of late. Just on 989 for ET, you guys recently announced phase III plans after speaking with the FDA, and that program's gonna start mid-year. Can you walk us through some of the unique elements in that design, and in particular, the ability to shorten the typical registration requirements and the implications of having VAF as a secondary endpoint here?
Yeah. Thanks, Brian. I'll try to get to all your questions. Obviously, just in terms of stepping back for a second, if you look at the sort of company 3 verticals, there's hematology, solid tumor oncology, and then immunology. In the hematology vertical, if I can put it that way, obviously myeloproliferative neoplasms are front and center. It's something that been the DNA of the company since the beginning, and something, you know, in the correct way we sort of wanna own going forward. The sort of research frame mindset there is mutation-specific therapies now. Moving beyond more broad sort of JAK-STAT inhibition, even in terms of nuances there, but really going to mutation-specific therapies. The first one in that journey is the mutant CALR antibody 989.
You know, to talk about specifically on ET on this question, I'm sure you'll come to MF next. ET is where we went first with the antibody. It's about, if you look at mutant CALR in that setting, it's about 25% of all of ET. It's a very clean environment to study it in because we have such a sensitive pharmacodynamic marker in platelets. It just gives you a very quick, clean read, it's something we utilized to the meat of your question going forward with the FDA on the study design, and it really helped us. I just wanna also, in terms of stepping back in this nearly 30 years I've been dealing with regulators and with the FDA, this is about the most collegial interactions I've ever had, and they're really interested in working with us and helping us.
We have breakthrough designation as well. I think the step back there is, you know, 16 years ago, we were the inventors of the endpoints here in certainly in myelofibrosis with SVR35 and symptoms. You know, those were ruxolitinib-driven and have remained the endpoints over the last 15+ years. There's a recognition from the FDA that this is a space we know well and can work well together. With the nine eight nine antibody in ET, we'll have an updated EHA. At ASH, we had approximately, I think, 50 patients of data, and 35 of those had 24 weeks follow-up. At this EHA update, it's quite substantive. There are 110 patients, and about 60 of those have, you know, doses greater than 750. It's a really substantive data set.
If you look deeper into that data set, and you're not looking at doses per se, but for the type 1 mutation, there's about a 92% complete hematologic response rate in the abstract. Then for the non-type 1s, it's in the 30%-40% range, which is something we knew straight off. It comes to your question, you know, what happened with the study design? The principle we wanted to get to was to make a very user-friendly study for physicians and patients. We wanted an all-comer study, and we wanted to try encompass both type 1s, which are uniquely sensitive, but non-type 1s in the same study, and then use a dose schema that could be rapidly titrated.
What we did and worked with the FDA to get to is it's an all-comer, so sites don't have to worry about whether they type 1, type 2, non-type 1, type 1-like. It's quite a complicated arena. You can put everybody on. We'll do the mutation-specific testing, obviously, and there's stratifications there. Everybody starts at 750 milligrams. It's those control rates I talked about in type 1. Then at cycle 2, day 1, day 29, if they haven't hit the 400 or below threshold, they immediately dose escalated to 2,500. We expect, you know, just about all the type 1s will be okay at 750, and then for the non-type 1s, a great proportion will need that dose escalation.
That was a great achievement. It's very user-friendly. It's easy to operationalize. The second thing was we get control very quickly, we managed to convince the FDA that we don't have to wait what is standard with other sponsors, 52 weeks. We can actually measure the endpoint at 24 weeks. It's complete hematological control for at least 12 weeks. You have to if you think that through, you have to have control by 12 weeks to get to 24 weeks. Platelets below 400, white cells below 11,000, no thrombosis, no bleeding. We're confident in that design. We like the setup. It's second-line ET versus BAT-OM, which we estimate will be Hydrea and anagrelide and interferons, and actually quite a decent proportion we think will be retreated with Hydrea.
In certain parts of the world, interferon use is increasing as well. We like the setup. It's a good study. It's literally about to start.
Excellent.
Yeah.
I guess where do you stand with the regulatory alignment in MF? I know there's maybe some principles from ET that can apply, but there's obviously not as readily available a rapid biomarker for response. Maybe talk us through how you're thinking about the MF path forward in second line initially.
Right.
Those discussions are entailing.
No, you're right. I mean, you teed it up perfectly. It's a little bit of a different milieu, right? We don't have a sensitive pharmacodynamic marker like platelets. There's spleen control, there's symptom control, there's VAF reduction. I didn't answer your VAF question on ET.
Yeah.
I'll come back to it. There's VAF reduction, but it's not as simple to titrate, so it's a little bit of a different construct. At EHA, again, we have quite a substantive update. I think there'll be about 80 patients of data at the meeting. A good proportion of those will have 24 weeks of follow-up in second-line MF, maybe you know, 60-odd patients there. And we're in the same territories on what are the standard responses in terms of SVR and symptoms. What we have with this drug that's unique is anemia response as well. In the abstract, you'll see a 58% anemia response rate, and that talks to disease modification aspects thereof.
Our ongoing assumption for the immediate question is that we'll be in the old world of SVR35 and symptoms. In that respect, we are okay, but it's not moving the field forward. What we'd like to do is have a healthy discussion with the FDA around a new endpoint in MF, in terms of registration studies, but it's actually been driven by the European LeukemiaNet for nearly a decade. They've published 3 times on what a composite endpoint could look like. In fact, they make a very strong argument that if you do a composite on hemoglobin, on blast count, on platelets, on spleen, it's actually more directly correlated with overall survival and leukemia-free survival than the old endpoint SVR35
a nd symptoms. That's been driven extraneous to Incyte by opinion leaders in the field. We'll see if we can get the FDA there.
Do you think the FDA is open to it?
I think they are. I think they want to try and move the field forward. They've realized that TSS50 particularly holding to that and trying to beat drugs and symptoms has proven very difficult, even for us with some of the combos. I think they are, and we'll hopefully have agreement sometime a little after the middle of the year and be able to tell you publicly on the third quarter call where we are. That's the desire and where we wanna be.
Control arms next, some of the other.
Speaking on MF.
JAKs.
Right. The main interest in the field is exactly what you just said. People want to see it against JAKs. It will probably be a BAT arm that incorporates ruxolitinib, litnirib, fedratinib, momelotinib, pacritinib, maybe even, you know, some HYDREA and danazol, like, lenalidomide, et cetera. That will be the control arm in second-line MF. It will also be IV. Beyond the endpoint, the next thing to agree on is dose. This is also tricky here because we don't have that PD marker.
Yeah.
One of two things, maybe more. One is we just go with a higher dose across the board if we do an all-comer study, come to an agreement based on our modeling. We'll have extensive modeling on what a higher dose could look like. Potentially, in this area, do a dose by mutation. Have a dose for type 1 and a dose for non-type 1. We'll have a test that can turn that around pretty quickly and be able to do that. That'll be the meat of the discussion, what the best way to do that study is.
Okay.
in terms of the dosing paradigm. Again, we'll communicate that when we have it. Just on the VAF endpoint in ET, because you asked earlier, it was the FDA who brought it up. They said, "You know, why this is disease-modifying. Why don't you put it in?" We have. We have pretty good data we'll show at EHA on correlating 25% or greater VAF reductions with heme response. There's some validation going on already. The same thing in myelofibrosis. If we get to a composite endpoint that has sort of blast, platelets, hemoglobin, you know, spleen control, we may have a molecular endpoint there as well to show. That's where we like to be with the field currently.
Okay. You mentioned EHA a couple of times, and you alluded to the additional data we're gonna see there, and we saw some additional data in the abstract, which looked very much.
Yeah.
aligned with what you've presented before. Anything more that we should be looking at, looking for at EHA across the MF and ET program that you think we should-
Yeah, I think-
point out? Maybe also, you know, there's been some competitive updates as well coming out of the EHA abstract, I'm just curious if you have any views on.
Sure.
on that.
You know, just very quickly, we got 3 presentations at EHA, an MF oral, ET poster, translational poster is really important, has single-cell sequencing data on megakaryocytes, on peripheral blood mononuclear cells, on myelofibrosis. I would look at that because it talks to disease MOA there. There's also about 20 patients worth of JAK-ineligible patients in that abstract. At the meeting, I think about 15 of those 20 have 6 months of follow-up. You'll get some sense of what a first-line population looks like, although the first-line data will present at the end of the year, so that'll be interesting as well. In terms of competitors, you know, we've seen the Ajax abstract looks really good in terms of SVR and symptoms.
What we're interested selfishly on what does it look like in the mutation-specific population, particularly mutant CALR. We know across the board our own data in the very small public dataset. JAKs don't do well in mutant CALR. They're not as active. We'll see what AJAX does there, and we wanna look at their AE profile because we know if we use high-dose ruxolitinib, for example, we could achieve the very similar SVR and symptom control, but you would run into quite significant anemia. We wanna just look at their profile there. Just to be clear, we're in a different mind frame. We, you know, we really think about mutation-specific therapies as the way forward, which is why, you know, we're not in that space currently. Our own V617F is sort of struggling along with the formulation.
We switched to an ASD now. Hopefully, we'll get better exposure and be able to hit IC35. We have next gen backups, we have a Prelude Therapeutics option deal on their lead and their backup. This is a space we're also extremely interested in, V617F specific therapies. It really opens up PV extensively. The Ajax Therapeutics dataset we'll look at, we're not sure if Johnson & Johnson is gonna have an effect or not on their bispecific. We have a bispecific in the clinic as well.
Yes.
There's some earlier efforts on siRNA in the space and vaccines, but I think they're a bit early to speak about.
Okay.
Yeah.
Got it. I know you're starting with IV, but you've made a lot of progress towards a subQ formulation. You recently reported that you had some success in healthy volunteers. Can you just help us envision what are you seeing? What kind of profile would constitute success here? Are you doing any additional formulation work? Is there sort of a concentration goal that you have?
Yeah.
Here with the I know you have the device that could enable at-home delivery of a subQ. I guess, how are you thinking about putting all the pieces together in terms of concentration, dose level, any reformulation, and what you guys are seeing so far that gets you as encouraged as you are?
I think you hit the main points, Brian. The subQ is really important from a patient perspective, right? In ET particularly, you know, people are generally well, don't necessarily wanna go to clinics or even infusion centers for years on end. Ultimately, getting to a subQ there is really key to our strategy and plan. We started in healthy volunteers to get bioavailability data. We completed that. We like what we've seen from a BA perspective, and we're currently going into patients now to sort of do the same thing, get more bioavailability data, et cetera. We know from the get-go, just to be clear, that we're not gonna be able to encompass these doses in pens. We went in with a device very early.
We've got this partnership with an FDA-approved device enFuse that can hold up to 25 ml. The amount you have in dictates how long that takes to infuse. Low amounts, 10 minutes, high amounts, 20 minutes to get it in. You take it off and dispose of it. You're right. There are two aspects. There's bioavailability. If you wanna ballpark bioavailability, IV to subQ, people generally want in the 40%-60% range, we're happy where we are without telling you what the exact number is. The next aspect is concentration. You have, you know, certain amount of milligrams per ml, and if you do those two calculations, you wanna be able to encompass your top dose in a single device.
We're comfortable we'll get to where we want in a single device, but it'll be towards the top end of the 25 ml, right, for you. We knew that going in. If you look competitively now, and we're taking at face value what MorphoSys have said, obviously, I think the R&D is about to go in. They're talking about, you know, more potency for non type one, and then in non-human primates, a 15-day half-life, so it could be a Q 4-week subQ. Our next gens are thinking about that as well. That's a good desirable profile to get to. Potentially, I'm not sure they know their dose or bioavailability. It's too early, but you could start thinking about can you then encompass those in a easier-to-use pen type formulation.
The second-line ET registration studies IV to start, should get across the finish line and launch in 2029. We have an agreement with the FDA to do bridging work. We should have a subQ available within 6 months of that launch. Second-line MF is likely to be IV as well given the timing 'cause we wanna go fast. Our first-line MF study we wanna do with a subQ from the get-go.
Great. That's super helpful. I promised I wouldn't spend the whole time on 989, so maybe we'll shift gears, but maybe stay on myeloproliferative neoplasms and initially before we move to I&I. You alluded to your own V617F. You have this new ASD formulation. Can you just give us a sense of, like, how that's going so far in the clinic and maybe what the key signals you're gonna be looking for out of that in the back half of this year?
Yeah.
To make a go, no-go decision on that asset versus moving with some of your next gens or with Prelude?
Yeah. No, I mean, firstly, again, it's incredibly important to us. V617F opens up, you know, the rest of MF particularly, but all of PV. Again, mutation-specific approaches are key. It's been frustrating. We knew we didn't have the optimal formulation. We've pushed it in the clinic. We can't get sufficient exposures to hit the target hard enough. We've just switched to ASD, and we're testing that now. This year, though, if we present data at the end of the year, it'll be on the old formulation, that'll be more like a 2027 dataset. If this doesn't get there because the target's so important to us, as you alluded to, we have next gen, we have the Prelude option deal, which is still open. I think it was 15 months when it was signed.
The R&D is in there on their lead. They have backups as well. You know, this is not a target we wanna miss out on.
Okay.
It's key to us. I don't know if our lead's gonna be able to give us what we need.
Okay.
We'll see.
That's good.
Yeah.
It sounds like you have a lot of different.
Right.
type of options.
That's why we have options. Yeah.
You recently launched, or are in the process of launching Jakafi XR.
Yep.
I guess can you give us any flavor of just what the early days are looking like in terms of receptivity? Any surprises in the way it's being used or, Then just how are you thinking about what would get you to that kinda upper end of the, I think, 15%-30% patient conversion range that you and Bill have talked about?
Yeah. It's just the principle. I have PTSD from this. We got a C- CRL. Now we all celebrate we got across the finish line.
Right.
It was not easy. We're there, and we've launched, as you said. We priced it at parity to IR, that's important. There's no issue for payers in that respect. The key is formulary coverage, you know, trying to get upwards of 50% to 70% coverage as quickly as possible. You know, this year's contribution will be modest.
I don't know, $10 million-$20 million type thing. Next year will be the first full year with adequate formulary coverage, and, you know, we hope to see, you know, a year of potentially, like, $100 million in sales. Then upwards of somewhere in that analog of the 10%-30% range, you'd want to use 20% as the number we use in, which in, you know, 31 months, that's what we have left till the end of the LOE, is gonna be a whole lot of hard work to get there, right? If we achieve that, we then potentially have it through, you know, the early 2030s.
Yeah.
maybe up to 2034. You know, Bill's been talking about numbers. If you take that 20% of where we are on our top line, you know, we could have somewhere around a $500 million-$700 million product from RUX XR, and that would really help us, you know, to bridge that trough period.
Okay.
As Bill says, and he's right, you know, if the company's trading on Rux XR at that time period, we've got a lot of things wrong, right? We have to be beyond that.
Okay
at that point.
Yeah, yeah.
Um-
Yeah. Yeah, but
You know
Even a modest piece of.
Well.
Is still a meaningful bridge.
Yeah.
Shifting gears to, I guess, John, oncology, heme onc. You guys recently reported positive phase III data for tafasitamab in first-line DLBCL back earlier this year. How are you guys thinking about the opportunity for the drug in that setting and, like, the key differentiating features versus standard of care? What should investors be focusing on for your upcoming ASCO presentation?
Right. so quick advertisement. It's a plenary oral at ASCO on Saturday. It's a plenary oral at EHA like a week later. Obviously the academic community's interested. It's the second positive study in first-line diffuse large B-cell lymphoma in 25 years.
Yeah.
Hazard ratio reported in January 0.75, P value 0.019. Different from the POLARIX study in that it's a little bit of a worse population, so we IPI 3-5. They were 2-5. We're about 30% ECOG 2 or above. They were 16%. Those are the major differentiators. 899 patients. That's a, you know, it's a curative, potentially curative population, really important data set. We'll show you at those presentations, all the other endpoints, event-free survival, et cetera. Very important focus on, I guess, two things. One is, cell of origin data. It's about 50% germinal center, 50% activated B cell. The POLARIX data is good. It's on a billion-dollar run rate, but it's used almost exclusively in ABC subtype because the germinal center hazards were basically 1.
That's in keeping with its MOA. We have good data in both data sets, so I think that's one differentiator, both cells of origin.
The other thing to look at, people are very focused on the 2-year PFS, EFS data because if you don't relapse within 2 years, you're usually cured.
of this condition. We'll show you that two-year split as well, and then we'll show you overall survival data as well. Really good for patients, really, you know, great to have a positive phase III in the setting. You know, Bill and the company have been conservative because of the entire market here.
Yeah.
their bispecifics coming, et cetera.
We think this will add to what we already have in somewhere around the $300 million-$400 million sort of range. There are 30,000 patients every year with first-line diffuse large B-cell lymphoma in the U.S. 50% still get R-CHOP, probably the lower IPIs in the germinal centers.
There's a clear opportunity, but we've been measured in how, what we think the uptake will be.
Got it. Can you talk about your latest expectations for povorcitinib in HS and maybe just what the uptake curve there could look like, where it fits in, and how potential competitor data later this year could shape that?
Yeah. you know, I think we probably did that endpoint too early when we presented last February. I mean, you can't change it once you declare a 12-week endpoint. The reason I say that is when you saw the 54-week update's looking really good, right? The HiSCR rates are where biologics are. Pain control is probably the best of, in the class and beyond. Draining tunnel data is good. The setup is really good. We think there are about 300,000 patients with HS. About 200,000 get treated, at a, you know, if you want to, at a branded, say, of 35,000 a year, you have a, you know, total addressable market that's upwards of, you know, between $7 billion-$8 billion. There are 3 groups of treatment. There's conventional therapy, antibiotic steroids. There's TNF, and then there's IL-17s.
We have data in both pre-biologic and post. That's our desire in terms of getting the label in both, and we want to be potentially used in both. You know, Bill spoke about numbers on various calls of, you know, around $500 million here. We'll launch early next year, so we should have a full year in 2027. We want to be used in both settings, pre- and post-biologic. That's the setup. The data looks good to support that. We don't think that's a hyperbolic number to achieve there. If you add vitiligo and then PN, the 3 indications, and should we get them all, talking about a $1 billion or north of $1 billion opportunity for povorcitinib for us.
Lastly, where does OPZELURA then fit in? I know you recently-
Yeah
expanded that study. Some of the doc feedback we've heard has been there's some intrigue. It's just given the.
Yeah
number of older patients
The anecdotal feedback's great. The study enrolled so well that adding 100 patients to each study has made no difference on timelines, we did that. What we really wanted to do is control the placebo response rate. There's no competitor in mild HS. We're the only ones going after it. It's abscess and nodules up to 10 and no draining tunnels, there could be a significant placebo rate, having a higher number could help there. The driver was easy to do. It's enrolling like gangbusters, control placebo response rate. Opportunity is another few hundred million on top of OPZELURA, important. Again, will give us that topical to oral solution in HS. Topical OPZELURA for the mild, povorcitinib for the, you know, moderate plus.
Okay. Lots more we could cover, but unfortunately, we're out of time.
No, thank you for having us.
Thanks so much.
It's been a pleasure.
Really appreciate you being here. That was great.