Incyte Corporation ($INCY)

[Audio Gap] presented by their Chief Medical Officer, Steven Stein. So thanks so much for joining us, Steve.

Thanks for having. It's good to be here. So a lot to cover. So -- and I don't want to spend the whole time on 989 because I know you have just a few other things in your pipeline.

But I do want to 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. Maybe just on the 989 for ET, you guys recently announced Phase III plans after speaking with the FDA, and that program is going to start midyear. 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.

Yes. Thanks, Brian. I'll try to get to all your questions. So 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, mitoplitive neoplasms are front and center. It's something that has been the DNA of the company since the beginning and something in the correct way, we sort of want to own going forward. And the sort of research frame mindset there is mutation-specific therapies now. So moving beyond more broad sort of JAK stat inhibition even in terms of there, but really going to mutation-specific therapies. And the first one in that journey is that you can INCA 989, and to talk about specifically on ET on this question, I'm sure you'll come to MF. But IT is where we went first with the antibody. It's about -- if you look at mutant here in net settings about 25% of all of it. It's a very clean environment to study it in because we have such a sensitive pharmacodynamic market in platelets. It just gives you a very quick clean read. And 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 wondered also in terms of stepping back in the 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. But I think the step back there is 16 years ago, we were the inventors of the endpoints here and certainly in myelofibrosis with SVR35 in symptoms. Those are ruxolitinib driven and have remained the endpoints over the last 15-plus years. So there's a recognition from the FDA that this is a space we know well and can work well together. So with the antibody in ET, we'll have an update at EHA. At ASH, we had approximately, I think, 50 patients of data and 35 of those at 24 weeks follow-up, at this EH update, it's quite substantive. There are 110 patients and about 60 of those have doses greater than 750. So it's a really substantive data set. And 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 tract. And then for the non-type 1s, it's in the 30% to 40% range, which is something we knew straight off. So it comes to your question, 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. So we wanted an all-comer study, and we wanted to try encompass both type 1s, which are uniquely sensitive but nontype 1 in the same study and then use a dose scheme that could be rapidly titrated. So 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're 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, in the stratifications there everybody starts at 750 milligrams. It's those control rates I talked about in type 1. And then at at cycle 2 day 1, day 29, if they haven't hit the 400 or below threshold, they immediately dose escalated to 2,500. So we expect the all -- just about all the type 1s will be okay at 750. And then for the non-type is a great proportion will need that dose escalation. And then it's the other -- so that was a great achievement. It's very user friendly. It's easy to operationalize. The second thing was we get control very quickly. So 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. So it's complete hematological control for at least 12 weeks. So you have to then -- if you think that through, you have to have control by 12 weeks to get to 24 weeks. And then sort of platelets below 400, white cells below 11,000, no thrombosis, no bleeding. So we're confident in that design. We like to set up a second line versus BAT arm, which we estimate will be Hydrea and Nabrilidand 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. So we like to set up a good study, and it's literally about to start.

Excellent. And 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 and what some of those discussions are entailing.

You're right. I mean you teed it up perfectly. It's a little bit of a different male, right? The -- we don't have a sensitive pharmacodynamic marker like platelets. Obviously, there's spleen control, there's symptom control, there's VAF reduction I didn't answer your VAF question on It'll come back to it. There's that reduction. But it's not as simple to titrate. So it's a little bit of a different construct. So 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 maybe 60-odd patients there. 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. So in the abstract, you'll see a 58% anemia response rate and that talks to disease modification aspects thereof, so like our ingoing assumption for your question is that we'll be in the old world of SVR35 and symptoms. And 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 in terms of registration studies, but it's actually been driven by the European leukemia network for nearly a decade, they've published 3 times on what a composite endpoint could look like. And in fact, they make a very strong argument that if you do a composite on hemoglobin, on blast count, on platelets on spleen is actually more directly correlated with overall survival and leukemia-free survival than the old endpoint SVR35 in symptoms. And that's been driven extraneous to inside by opinion leaders in the field. We'll see if we can get the FDA FDA is open to it. I think they are. I think they want to try and move the field forward. They realize that TSS-50 particularly holding to that and try to be dragon symptoms has proven very difficult even for us with some of the combos I think they are we'll hopefully have agreement sometimes a little after the middle of the year and be able to tell you publicly on the third quarter call, where we are. So that's the desire in where we want to be

Control arms. Next -- some of the...

Right. The main interest in the field is exactly what you just said. People want to see it against Jack's -- so it will probably be a BAT arm that incorporates ruxolitinib, fedratinib momelotinib, pacritinib, maybe even some Hydrea and danazol, lenalidomide, et cetera but that will be the control arm in second line MF. It will also be IV. So beyond the endpoint, the next thing to agree on his dose. And this is also tricky here because we don't have their PD marker. One of 2 things may be 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 an extensive modeling and what a higher dose could look like or potentially in this area, do a dose by mutation. So have a dose for type 1 in a dose for non-type 1. And so we'll have a test that can turn that around pretty quickly and be able to do that. They will be the meat of the discussion, what the best way to do that study is in terms of the dosing paradigm. And again, we'll communicate that when we have it. Just on the VAF endpoint in ET because you asked earlier, it was the FDA, we brought it up. They said, Why? This is a disease modifying, why don't you put it in and we have -- we have pretty good data, we'll show at EHA on correlating 25% or greater VAF reductions with heme response. So there's some validation going on already. So the same thing in in myelofibrosis, if we get to a composite endpoint that has sort of blast, platelets, hemoglobin, spleen control, we may have a molecular end point there as well to show. So that's where we like to be with currently.

You mentioned EHA a couple of times, and you alluded to the additional data we're going to see there, and we saw some additional data in the abstract, which looked very much aligned with what you've presented before. more that we should be looking at, looking for at EHA across the MF NET program that you think is out, and maybe also, there's been some competitive updates as well coming out of the EHA abstract. So I'm just curious -- do you have any views on...

So just very quickly, through presentation or an MFR ET post translational process is really important, has single cell sequencing data on megakaryocytes on peripheral blood mononucleosides or marofibrosis. So I think I would look at that because it talks to the disease MOA. There's also about 20 patients worth of JAK ineligible patients in that abstract. And then at the median, I think about 15 of those 20 have 6 months of follow-up. So you get some sense of what a first-line population looks like, although the first-line data were present at the end of the year, so that will be interesting as well. In terms of competitors, we've seen the Ajax abstract looks really good in terms of SVR and symptoms. What we interested selfishly and what does it look like in a mutation-specific population, particularly mutant Kala. We know across the board, our own data and a very small public data set that JAKs don't do well in Mutant Kalon. They're not as active. So we'll see what Ajax does there, and we want to look at the AE profile because we know if we use high dose racks, for example, we could achieve very similar SVR and symptom control but you would run into quite significant anemia. So we want to just look at that profile there. Just to be clear, we're in a different mine frame, we're really thinking about mutation specific therapies at the way forward, which is why 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 IC 35. We have next-gen backups and we have a prelude option deal on their lead and their backup. So this is a space we're also extremely interested in specific therapies, it really opens up p-vera extensively. So the AGX data set, we'll look at -- we're not sure if J&J is going to have an effect or not on their bispecific however, bispecific in the clinic as and then some earlier efforts on SR An space and vaccines, but I think they're a bit early to speak about.

Got it. I know you're starting with IV, but you've made a lot of progress towards a subcu formulation. And you recently reported that this was -- you had some success in healthy volunteers. So can you just help us envision what sort of -- what are you seeing? What kind of profile will constitute would constitute success here? And are you doing any additional formulation work? Is there sort of a concentration goal that you have here with the -- I know you have the device that could enable at-home delivery of the subcu. 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?

Yes. No, I think you hit the main points, Brian. The subcu is really important from a patient perspective, right? In ET, particularly people are generally well, I don't necessarily want to go to clinics or even in fusion centers for years on end. So ultimately, getting to a subcu 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 going to be able to encompass these doses in pens. So we went in with the device very early. We've got this partnership with an FDA-approved device infused that can hold up to 25 mL. The amount you have in Dictatolong that takes to infuse. So low amounts, 10 minutes, higher amounts, 20 minutes to get it in, you take it off and dispose of it. You're right, there are 2 aspects. There's bioavailability. If you want to ballpark bioavailability, IV to subcu people generally want in the 40% to 60% range. And so we're happy where we are without telling you what the exact number is. But the next aspect is concentration. So you have a certain amount of milligrams for ML. And if you do those 2 calculations, you want to 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 will be towards the top end of the 25 ml, right, for you. And so we knew that going in. If you look competitively now, and we're taking at face value, what Temora said, obviously, I think the R&D is about to go in they're talking about more potency for nontype 1 and then in nonhuman primates, a 15-day half-life. So it could be a Q4 week subcu. So our next gens are thinking about that as well. So 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 an easier-to-use pen type formulation. The second line ET registration study is IV to start should get across the finish line and launch in 2019. We have an agreement with the FDA to do bridging work. We should have a subcu available within 6 months of that launch. Second-line MF is likely to be IV as well given the timing because we want to go but our first line MF study we wanted to do with the subcu 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 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 going to be looking for out of that in the back half of this year to make a go/no-go decision on that asset versus moving with some of your next gens or with Prelude?

Yes. No. I mean, firstly, again, it's incredibly important to us. So 617 F opens up the rest of MF, particularly, but all of Vera, and 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 AS and we're testing that now. This or though, if we present data at the end of the year, it will be on the old formulation, so there will be more like a 27 data set. If this doesn't get there because the target is so important to us, as you alluded to, we have next gen and we have the Prelude option deal, which is still open I think it was 15 months when it was signed, the IND is in now and they lead their backups as well. So this is not a target we want to miss out on, it's key to us. I don't know if our lead is going to be able to give us what we need, we'll see

That's good. It sounds like you have a lot of different -- that's all options. And then you recently launched or in the process of launching Jakafi XR 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? And then just how are you thinking about what would get you to that kind of upper end of the, I think, 15% to 30% patient conversion range that you and principal. So...

I have PTSD from this. We've got a CRL, but now we're all celebrate. We've got across the finish line at -- it wasn't easy. But we're there, and we've launched, as you said. We priced it at parity to that's important. There's no issue for payers in that respect. The key is formulary coverage, trying to get upwards of 50% to 70% coverage as quickly as possible. 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 we hope to see a year potentially like $100 million in sales. And then upwards of somewhere in that analog of the 10% to 30% range you want to use 20% as a number we use in, which in 31 months, that's what we have left till the end of the is going to be a lot of hard work to get there, right? If we achieve that, we then potentially have it through the early 2030s, maybe up to 20 Bill has been talking about numbers. If you take that 20% of where we are in our top line, we could have somewhere around the $500 million to $700 million product from Rux XR, and that would really help us to bridge that trough period. As Bill says in his right, if the company is trading on rux XR at the time period, we've got a lot of things wrong, right? So we have to be beyond that at point. Yes.

We've been a modest piece of is still meaningful bridge Shifting gears to, I guess, on oncology, Hema, you guys recently reported positive Phase III data for tafacitumab in first-line DLBCL back earlier this year. How are you guys thinking about the opportunity for the drug in that setting and the key differentiating features versus standard of care? And what should investors be focusing on for your upcoming ASCO presentations SP-2 Right?

So quick adjustment, it's a plenary oral at ASCO on Saturday. It's a plenary oral like a week later. So obviously, the academic community is interested in. It's a second positive study in first-line diffuse large B-cell lymphoma in 25 years. Hazard ratio reported in January, 0.75, p-value 0.01 in different from the poor study in that it's a little bit of a worse population. So we IPI3to5. They were 2 to 5. We're about 30% ECOG 2 or above. They were 16%. So those are the major differentiators, 899 patients -- it's a curative potential cure population, really important data set. We'll show you at those presentations all the other endpoints of entry survival, et cetera. Very important focus on, I guess, 2 things. One is cell of origin data. It's about 50% germinal center, 50% activated B cell. The POLARx data is good. It's on $1 billion run rate, but is used almost exclusively in ABC subtype because the germinal center hazards were basically one, that's in keeping with its MOA. We have good data in both data sets. So I think that's 1 differentiator, both sales 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 usually cured of this condition. So we'll show you that 2-year split as well, and then we'll show you overall survival data as well. So really good for patients, really great to have a positive Phase III in the setting, the bill in the company have been conservative because of the entire market share. We know their bispecifics come in, et cetera. We think -- this will add to what we already have in somewhere around the $300 million to $400 million sort of range. There are 30,000 patients every year with first-line diffuse lose B-cell lymphoma in the U.S., 50% still get our chat probably the lower IPIs in the germinal centers. So there's clearly 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 Provo 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?

Yes. So I think we probably did that end point too early when we presented last February. I mean, you can't change them once you declare 12-week end. The reason I say that is we saw the 54-week update looking really good, right? The Hisco rates or where biologics are pain control is probably the best in the class and beyond draining tunnel data is good. So the setup is really good. We're thinking about 300 patients with HS, about 200,000 get treated at -- if you want to add a branded say, of 35,000 a year, you have a total addressable market that's upwards of between $7 billion and $8 billion. There are 3 groups of treatment. There's conventional therapy antibiotic steroids there's TNF and then there's IL-17. We have data in both prebiologic and post. That's our desire in terms of getting the label in both. And we want to be potentially used in both Bill spoke about numbers on various calls of around $500 million here. We'll launch early next year. So we should have a full year in 7 and we want to be used in both settings, pre and post biologic. So 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 it and PN, the 3 indications. And should we get the more talk about $1 billion or north of $1 billion opportunity for Pogo for us.

And then lastly, where does Apsalura then fit in? And I know you recently expanded that study some of the dock feedback we've heard has been symmetries just given another file their patients I think total feedback is great. The study enrolled so, so well that adding 100 patients each study has made no difference on time line. So we did that. But what we really wanted to do is control the placebo response rate. So there's no competitor in mild HS. We're the only ones going after it. It's absence modules up to 10 and no draining tunnels. So there could be a significant placebo rate. So having a higher number could help there. So the driver was easy to do. It's enrolling like gangbusters, control placebo response rate. Opportunity is another few hundred million on top of Opal so important. And then again, will give us that topical to oral solution in HS, topical Opsalura for the mild Povoforthe moderate plus.

Lots more we could cover. But unfortunately, we're out of time.

Thank you so much. here. That was great.