Good morning, everyone. My name is Ed Surgeru, senior biotech analyst at Barclays. My pleasure to have Insight. Joining us today, day two of our conference with me, I have Bill Murray, president and chief executive officer at Insight. And to my far right, we have Pablo Cognini, head of R&D at Insight. Welcome to our conference. Bill, I'm sure most of our listeners are fairly familiar with Insight, but maybe provide some introductory remarks, maybe some of the key points around the business in the pipeline over 2026.
Yeah, I mean, we think about Insight across three dimensions or therapeutic areas, hematology, which I would describe as the central identity of the company. We have an emerging solid tumor oncology business that really started to declare itself in 2025. at ESMO with our G12D inhibitor for pancreatic cancer and our TGF beta by PD1 for colorectal cancer, which are now in frontline phase three studies. And then we have an immunology business that is anchored today by a topical JAK inhibitor called Opsilora. We expect to get an approval for povacitinib at least by the end of 2026, early 2027. And so in that area, we'll have a topical to oral solution, what I think is an advantage across three different immune-mediated skin conditions. We think about the business in two parts. We have a core business, X-Jackify, which by 2030, we expect will be as big as Jackify. That business in 25 did about a billion two, was up 50% year over year. Maintaining the health of that business is critical to navigating this transition in 2029 when we lose exclusivity for Jackify. And the other part of the business is our pipeline, and we have seven assets in development where 80% of our R&D investment is centered on, and those programs are continuing to declare themselves. And so we take our core business, we layer on our pipeline, and the company has the potential to go way beyond Jackify and essentially set a new high-water mark for insight. That's how we think about the business. The last point I'd make as it relates to business development, just like at any company, it will be used as a multiplier and to extend or strengthen the core business.
Great. Thank you for that. Let's maybe start with Jackify and think about sort of, you know, it's a major source of revenue today, as you pointed out, but not sort of the growth engine longer term. When you think about sort of how you internally measure sort of success, maybe post-Jackify, is it about revenue replacement, you know, pipeline advancement, margin preservation? How do you think about sort of the bar for success for the replacement if you will ultimately have a Jackify?
Sure. It's a good question. We're not looking for a one-for-one replacement on Jackify. If you really think about what we're solving for, it's top-tier growth post-29 and durable revenue earnings and cash flow, which is to say we want to minimize our LOE exposure. And there are two parts to the solution. I mentioned this core business, XJackify. That business has the potential to grow at a 15% to 20% five-year kegger. So between now and 2030, it should approach $3 billion to $4 billion. And that is about managing the business on a day-to-day basis at a very detailed level. Now, growth is not linear. What's important in that core business is four product launches over the next 12 to 18 months. Jackify XR, frontline DLVCL for Monjuvi, where we just recorded top, well, not top-line results, but released the results of our study. moderate AD indication for Opsalora in Europe, which will be an important incremental growth driver, and then povacitinib. Those four launches are important in terms of continuing to drive our core business. And then as we look at our pipeline, we made a lot of progress in 2025. You know, when we started the year, we had no proof of concept data on 989. We had no proof of concept data on the G12D inhibitor or TGF beta by PD-1. We had no phase three data on Povacit or combination data with Nick Timbo and Jackify, at least from a safety perspective. We have all those things now. And so what it means is we have much more visibility into the growth profile of the company in order to go beyond Jackify. And we'll measure our success this year, next year, and the following year in terms of advancing those programs. But right now, we've fundamentally changed the shape of maturity of the pipeline. And I think it's probably more focused and strategically aligned than ever before. And then, like I said, the next part of that equation is always BD, which will, again, will be targeted and selective. And it will be used to extend the core, not looking to fill a revenue gap, looking to build a business. into the 2030s that is an all-weather business, essentially.
And obviously, one of the areas of focus for Insight is myeloprolivative neoplasms, right, given your position with Jackify. You presented some MASH data suggesting, you know, benefits across slain, benefits, symptoms, anemia benefits for your MCLR program. And when you think about conversations with regulators, you know, across these different endpoints, if you will, what do you think ultimately matters most for patients where if you think about sort of what a pivotal looks like, where you can really sort of highlight the benefits of like an MCAL-R program and population of patients with MMPs?
Yeah, it's a good question. I'll make a couple comments and then just turn it over to Pablo to expand. First, I think with the data that we shared at ASH at the end of the year, 2025 in both MF and ET, in this pretty sizable Phase I program. I think we've answered all the threshold questions on 989, our monoclonal antibody targeting in CalR. On the ET side, we have a very complete, a very high complete hematological response with pretty pronounced impact on VAP, so both the clinical and molecular endpoint. I think that the approval of 989 second-line NET is going to quickly reshape the use of hydroxyurea, which is an imperfect treatment. It's the best they have right now. On the MF side, whether it's spleen volume reduction, SVR 35, symptom relief, TSS 50, anemia response, what you saw in that phase one study is frontline efficacy in a second line setting. Right. And for hematologists out there, Jackafide has been a remarkable drug, made a big difference in patients' lives, but it's a trade-off treatment. You increase the dose, you control symptoms but cause anemia. If you don't increase the dose, you avoid the anemia, but you don't control the disease. And symptom relief is common in the treatment of MF, but molecular response is rare, and we have the potential for both with 989. We're going to be starting phase three studies. We expect to start phase three studies in the middle to the end of the year in both ET and MF, and we're currently in interactions with the FDA, and I'll let Pablo make a comment on where we're at.
So our goal, as Bill mentioned, is to start at least two phase three studies this year. We started conversations already with FDA. Those conversations have taken place, and we're finalizing the protocol for the second-line ET study, And the important thing is, what aspects are we reaching agreement with FDA? So we need to agree on the population. This study is going to be in all comers, both type 1, type 2, and non-type 1, type 2 patients. We are reaching agreement with the agency on the dosing strategy. We agree with the comments that we made that when you see the data that were presented at ASH, it seems like patients with type 1 respond at a lower dose. So we want to take that into account in this study. but we still want to keep keep one study uh the endpoint the primary endpoint is pretty straightforward here it's going to be some version of completely my logic response but what we're trying to do with the agency is two things we're discussing maybe accelerating the readout of the endpoint the traditional approach has been 52 weeks and then on the other side incorporate in some manner not as a primary endpoint but in some manner of as an endpoint to just get started with the clinical validation of AFIS and endpoint in patients with MPN. So those things will be, I'm confident, will be finalized by the end of the month. At the latest, we will present the details of the next earnings call. In the second half of April, we'll give you full details of the design of that study. In the second half of the year, as Bill mentioned, our intention is to start a second line MF study. Those conversations will take place soon with the agency, but we're finalizing a data package. And then we're making a push to start a first-line MS study, whether that's very late this year, early next year. It's a little bit in flux right now, but we're certainly moving as fast as we can. And I will be remiss if I don't comment real quick. The other important aspect of the development plan for 989 is the subcutaneous formulation that's going to enter the clinic this month in Healthy Volunteers. We're going to then move to patients as soon as possible. And by the second half of the year, probably early, late third, early fourth quarter, we'll have not only the formulation, but we'll have the device, the subcontinuous device that we intend to use at some point. We're going to incorporate as soon as we can into pivotal trials.
And I think I wanted to talk about the anemia response, particularly in MF. When you think about that, it looks like a differentiator to us relative to sort of what you see with JAK1s. Is it really maybe a commercial story, or could it be viewed as really just game-changing or transformative, I guess, for the patients that can see that anemia response benefit? How do you think that response gets positioned commercially?
Yeah, I would say that I mentioned earlier that hematologists will sometimes describe JAK inhibitors as tradeoff treatments. And it's because that anemia is a negative prognostic indicator for survival. In fact, if you look at patients with MF and severe anemia, their median survival is quite a bit shorter than those who have MF without severe anemia. The big difference is we're not just avoiding anemia, and I think Pablo speaks to this quite eloquently. It's proof of mechanism that not only is 989 shrinking the spleen and improving symptoms, but it's restoring normal bone marrow function and red blood cell production. So I think it's a crystal ball into how 989 works. I think the community is going to have to look at the totality of the data. It's not just about anemia. It's not just about the conventional endpoints, SVR 35 and TSS 50. But across the continuum, you have what appears to be a superior treatment to the current standard of care. And I think, you know, your comments about anemia are, like I said, really effectively describe the benefit that 989 provides relative to anything else that's available.
I think it's an important distinction, as Bill said, because there are drugs that seem to have some impact on anemia, probably because they're less potent than Jackify, and so they're a little bit less toxic for red-soled progenitors. What we showed at ASH is something fundamentally different. As you pointed out, in addition to the spleen shrink as a symptom improvement, we showed that more than 50% had really important improvements in anemia. We're talking about one and a half gram, two grams improvement in hemoglobin over time. And I think that one of the questions that has come up is that because of discontinuation with Jackify, the answer is no. We've talked about this before. Or we looked at patients without a prior washout, and the impact on our anemia is the same. And we looked over time, and the anemia keeps getting better many months after stopping So this is not discontinuous jackify, which is not to say that stopping jackify is not a good thing for the anemia, but the effect we're seeing is not jackify discontinuation. And the other important part of the story is when you look at in detail of what's going on in the bone marrow, we showed that we are shifting back to normal production of red cells. And that is basically one of the key elements of disease modification that we're seeing with 989. The bone marrow is starting to normalize again and starting to make normal red cells again,
and that's why hemoglobin goes up. Great. And maybe on the 05A program, the JAK, the V617F. You know, I think, you know, in our discussions, there doesn't seem to be questions around sort of mechanism or rationale, maybe more around sort of the formulation and whether or not this formulation can overcome limitations of the prior work. Maybe your thoughts around maybe level of confidence for the new formulation for 058 as you think about being able to kind of show, again clinical benefit with that program? Let me start. I am confident on the
mechanism. V617F is the driver mutation of this diseases. When you hit driver mutations hard enough you get positive clinical outcomes. I mean we've seen that over and over over the past 25 years. So the question is how do we hit it hard enough? 058 we knew entering the clinic there a couple of challenges and we made this very clear that the therapeutic window 4580 is relatively narrow it's not ideal we thought it was good enough and still do to achieve what we need to achieve we knew there was a solubility problem we put a formulation initially in the clinic that we thought addressed it it turns out we need something different we introduced the solid dispersion formulation this quarter and we will have data by the end of the year Based on the healthy volunteer data, I'm cautiously optimistic that we'll get to the exposures that we need to see evidence of clinical activity.
Now, we have two backup plans, one internal.
We have backup molecules that we think have improved properties over 058. Those are being advanced as fast as possible. And as you probably know, we signed an agreement with Prelude last year that gives us access to their V617F inhibitor programs. They're managing those programs. We have an option agreement. If at some point in the future they share the data with us, if the data looks strong, we have the option to acquire, fully acquire the program. So that's how we're addressing V617F. I think one or more of this approach is going to get us what we need.
Maybe switch gears to lymphoma and Tafacitimab with the update you provided for the frontline treatment in DLVCL. You know, you mentioned R-CHOP still, you know, very much used in that frontline setting. I guess, you know, how do you see the role of Tafacitimab if it was involving in that frontline setting?
The goal, as most people know, in frontline DLVCL is cure. 40% of people still don't achieve cure. As you know, that space is evolving. You have ARCHOP, which is just 50% of treatments. You have Polivi, and then, of course, at some point in the future of Kinley, or this year we should know whether or not it has utility in the front-line setting. We have a strong efficacy signal in terms of PFS. We'll release more data in 2026 in terms of activity in subgroups and a manageable safety and powerability profile. And so when you think about Monjuvi, think about the community setting, high-risk patients aren't on our trial. And it simply represents an add-on or intensification strategy. And to put in perspective for Insight, if we were to get a modest portion of the frontline DLBCL market, call it 10 or 15 percent, we could 2x the sales of Mongev on an annualized basis. And so I think it's going to play an important role. We don't need to take over the frontline DLBCL market. The data set that we're going to release in 2026 is a fairly competitive or very competitive data set. We'll submit to the agency in the first half of 2026, and we could have an approval at the end of 26, early 27, give or take.
Great. Maybe the INI franchise, with what we're sitting in, you have a couple of important pivotal data points this year. Maybe first in PN, how much better does POVO need to be relative to a Dupixent, if you will? And just if you think about sort of level setting expectations around that data set and how that can sort of play out or evolve.
I'll make a first comment and then turn it over to Pablo. I don't see, whether it's HS, PN, or vitiligo, sort of a fight to the death or a market share battle or an either or. I think what's lacking right now in those conditions is an oral anti-inflammatory. In HS, you can take a topical or systemic antibiotic and they get to jump all the way to an IL-17. In PN, there's no FDA approved oral. And I think there's an expectation in the dermatology community as it relates to sort of clearance and itch. With all these conditions in PN, I think it was made for JAK inhibitors. And so I don't really look at it versus Nemluvio or versus Depixin, but get the first FDA-approved oral JAK inhibitor for PN, and that's going to have a meaningful role in the treatment of that condition. I think the same is true in HS, and the same is true in Vitiligo. Do you want to add anything?
I'll just add one quick comment on PN. I always agree with Bill's comments. I think one of the things that public system does very well, and we've seen that both in HS and in the Phase 2 and 3 and in the Phase 2 in PN, is it works very fast. When you look at itch, two-thirds of the effect has about two weeks. And if you look at the median time to four points or greater itch improvement, at the higher doses, that's 19 days. That's a lot faster than 2P. And when you talk to dermatologists, they will tell you that 2P works, but it takes a long time to work, particularly when it comes to itch relief. And that's the key symptom in PN patients. So I think POV is a great drug for PN. obviously we're very very optimistic about the vitiligo results what we'll have them in the middle of the year and this speed which it works both in HS and PN I think are going to be obviously in addition to the fact that it's all going to be a key difference I think for patients. And in vitiligo you know
relative to Upsura is it going to be a different patient population complementary treatment how do you see those two sort of evolving in vitiligo?
Yeah, it's a good question. We'll have the only topical to oral backbone. And Opsalora has penetrated a fairly high percentage of the diagnosed and treated vitiligo patients who have a BSA involvement of less than 5%. But for people with a BSA of greater than 5, clearly an oral treatment is more practical than a topical one. And I think we have an advantage going into vitiligo, we're there now. We, of course, have the topical, assuming the data in phase three are convincing. I will expand that market in terms of diagnosed and treated because
you have an oral versus a topical. Maybe quickly on the TGF beta PD-1 biospecific program, moving into a pivotal study in colorectal cancer. I think that was a bit of surprise if you will to jump from from phase one to phase three. Maybe again talk about sort of you know what we could see from a differentiation or just data update that can maybe give us more confidence around sort of the the
pivotal plan around around the molecule. So I agree that historically you sometimes take an intermediate step. The reasons why we did this when you look at the phase one data, there's a couple of things that are unique. Number one, we drew 100 patients with MSS colorectal cancer. I mean, this is not the usual small 12 patient data set. So the point estimate for the response rate in that population, I think is a pretty solid number, which is about 15%, including a lot of patients with liver metastasis. And again, this is third, fourth line MSS colorectal. When you compare that with every other piece of data published with PD-1, PD-1 inhibitors, Pembro, Nevo, Atezo, the response rate to those agents is zero. Not low is zero. There are no responders. And even if you look at the recent combinations with novel CTLA-4 inhibitors in addition to PD-1s, they've seen responses, but none in patients with liver metastasis. We have. About half of our responders have liver mets. So that's the strength of the data. We think we have a drug in this population of patients. We combined with chemotherapy with Falfox-Pev and we showed that the safety is there, they're well tolerated together. So when the question came, is there enough substance here to initiate a pivotal trial? When you look at the history of development of PD-1 inhibitors over the past 15 years, you'll see that a number of times that they have response rate of single agents in the single digits to low teens when combined with chemotherapy in early lines of therapy that has delivered about eight or nine different approvals. That's the path we're following. We think that the strength of the single agent responses we've seen in late line combined with chemotherapy in first line will deliver a positive trial. So at the end of last year we initiated this study. The study is now accruing patients and we will provide an update on the data set in combination with chemotherapy towards the middle of this year, just to give you more clarity of what we've seen.
And when you think about portfolio construction, the company is going to take some calculated risks. If we're right, it's transformational. If we're wrong, we haven't bet the farm. I think Pablo's point about an intermediate step, given the breadth and depth of the Phase 1 data set, it made a lot more sense in this case to go into Phase 3.
Great. Just maybe lastly on the KRAS program, you know, the early data suggests, you know, meaningful activity. How are you thinking about sort of maybe going into maybe earlier line settings, particularly where you may see lower tumor burden for those patients? How are you thinking about that?
So the video that we showed, as you pointed out, is a single agent, second, third line. We also showed early data in combination with chemotherapy, ASCO-GI, showing that we can combine our G12T inhibitor with both main types of chemotherapy in first-line pancreatic cancer, GEMNAB and fulfirinox. So that's been established. On the basis of that, we are initiating a phase three trial in first-line pancreatic. We think that is the most important indication. We obviously are in a race with some competitors that are going the same path, and we need to get there as fast as possible. We'll provide an abdomen diet date in the second half of the year, again, just to give you a clarity of what we're seeing in terms of the combination with chemotherapy. At the same time, we're discussing internally what other indications should we prosecute with the 12D, and I think you alluded to much earlier lines like adjuvant therapy and perhaps other combinations. for doing a lot of that background work and you should expect an update on how we expand this
program in the second half of the year. Great. Bill, Pavel, thank you for your joining us, for your participation and hopefully you enjoyed the rest of the conference. Thank you very much. Thank you to our listeners as well. We'll be back shortly with our next session.