Great. Welcome, everyone, to the Piper Sandler Healthcare Conference. My name is Biren Amin. I'd like to welcome our next company. We have Immunome and their CEO, Clay Siegall. Welcome, Clay. Maybe if you could, we could start off with just the company's focus on Varegacestat , as well as the ADC platform. If you could just maybe provide an overview, and then we can go into some of the pipeline programs individually.
Sure. Thank you for the invitation to be here at the conference. Immunome is a company that is focused on targeted therapies for cancer. And by far, our pipeline is dominated by antibody-drug conjugates, but we also have a radioligand, and we have targeted small molecules such as Varegacestat , which you mentioned. So we don't do other types of cancer therapy that are exciting, like cell therapy or gene therapy, different infrastructure. So we're focused on antibody types of therapies, ligands, and small molecules that are targeted.
With Nirogacestat , clearly small molecule inhibitor of gamma secretase in a phase 3 study called RINGSIDE. What's the objective of Varegacestat in terms of targeting of patients with desmoid tumors?
So desmoid tumors is a disease, it's a type of cancer that there's been no therapy approved, literally forever, until Nirogacestat was approved by some fantastic work that a company called SpringWorks did, which is now acquired by Merck KGaA. And that drug was the first ever drug approved for desmoid cancer. And it is a gamma secretase inhibitor, but it's a very different chemistry, very different pharmacokinetics, different molecules than what we're developing. And so the goal of what we're developing with variegated statin is just to be a much better medicine for patients. And through my career, I've made a lot of medicines that are on the market. And the goal is always to do best you can for patients.
So in this case, we want something that's simple to use, easy, once a day, that has a much higher response rate, a much deeper tumor regression rate, and a lot of other types of endpoints. So the goal is just to make better medicine for patients.
And so the phase III is about to complete. Primary endpoint is progression-free survival. What are you hoping to see from the trial, and with Nirogacestat on the PFS endpoint, given the phase II data that's been generated with this drug?
You are correct. We're going to report on our phase III shortly. We have been guiding for two years and tweaking guidance. We have said that we're planning to unblind this quarter before the end of the year. It's not guidance anymore; it's a plan. You'll be hearing soon because it's almost the end of the quarter. We're very excited to put out our data. We will put out the top-line data and reserve some of the data for a suitable conference so that the physicians that prosecuted this trial will be able to stand up and represent the data, which is appropriate. We'll put out top-line data, and there'll be plenty of data put out that we'll be able to, so anybody looking at the data will be able to understand the gravity of it and how well it works.
We'll obviously try to frame the discussion. There's a lot of endpoints that are important. Progression-free survival is an endpoint that's important. It's in the DeFi study, which was the SpringWorks study. They did not hit their median PFS. It is highly unlikely we'll hit a median PFS. So you can look at hazard ratios, something like that. There are other endpoints that doctors are very keen to looking at. I've been making cancer drugs for 30 years. I've not met a doctor yet that doesn't say, what's the objective response rate? It's the first thing that the doctor asks. They ask it before PFS, actually. And so we're going to report top-line, we'll report ORR. You can't get around that. And especially if a PFS is, we did not reach our median PFS, the ORR becomes really important. And that's what doctors ask first anyway.
They'll also ask, so what's the median tumor reduction in patients? They want to know, they want to be able to tell their patients something. And so the numbers that were in the DeFi study for Nirogacestat f rom SpringWorks, now from Merck KGaA, were 41% objective response rate and 59% median tumor reduction. And they got approval, and it's the only drug available for desmoid. So those are the numbers that we have to do better than or else it's not a meaningful product. And we have our phase II data. Our phase II numbers were way in excess of those, much better. But you can't compare phase III to phase II. And so what we have to do is compare apples to apples. And so when their phase III FDA design and run study will be compared with our study, which will be unblinding very soon.
And then we'll have an FDA run study with the right endpoints and everything. And then you can compare and look at the endpoints, such as look at their 41% and 59% for ORR and median tumor reduction, and then you look at ours. It'll be pretty quick that folks will be able to know the difference.
It's interesting. You highlight ORR and median tumor volume reduction. Last month, we did a KOL call with an expert in the space, and he talked about also onset of response and the fact that patients on nirogacestat have to wait on average about six months in order to achieve a response. What are your thoughts in terms of onset of activity with Nirogacestat? Would you be able to differentiate on that? Because there's also, I guess, read-through that earlier the response, the potential for a higher and deeper response later on.
There's a lot of data. If you're a cancer patient, to go with what you say, what you want is you want to get a response as fast as possible, and with desmoid cancer, it's a little different than a lot of cancers I've worked with in the past. Some cancers that I've worked with, you don't live long. The median survival is short. In this disease, you live longer, but it's incredibly painful and difficult, so patients want to know how quick a drug will respond because it's so painful, and while desmoid cancer doesn't kill you like pancreatic cancer does really quick, it's an awful disease, and it affects a lot of young people, especially women in their 30s and things like that. It's a really bad disease. You don't want this disease.
And so that's why patients are asking, doctor, how long will it take before I feel better? And so we are capturing a lot of data. Not every piece of data will be in top-line. You have to save data for the physicians that have worked so hard on the trial for a long time on our phase III trial to present it and hopefully a podium presentation. So we'll do the best we can presenting data, and we'll preserve data for the doctors as well. So we'll do the best to manage both sides.
That's great. And then we talked about the efficacy side. How about on the safety side? What are the comparisons potentially with Nirogacestat? About 30% of the patients with Niro develop diarrhea where they have to dose interrupt, dose discontinue. Have you seen that with Varegacestat ?
So the phase II safety profile of Varegacestat , our drug, has obviously been presented. The phase III has not yet. So I can't today, we haven't unblinded yet, so I can't talk about the full safety profile. What I can say is we had a data safety monitoring board, which all phase III studies like this have. And it's something you work, you set up a DSMB, and it reports it to FDA if and when it needs to. The data safety monitoring boards can impact trials. They can stop trials. They can keep them going. They can do a lot of different things. But we have made, there have been no announcements, no press releases on any comments from DSMB. So I'm very pleased about that. That means there was not anything big. And our last patient was enrolled, I think, about 20 months ago.
We're doing well on any gross effect that you would have to put on a press release, and we have not on that. On the specifics of safety, I would say in my history of developing cancer drugs, I don't know any cancer drugs that have zero side effects. So we certainly will have certain side effects. And remember, these are really sick patients. So a lot of times there are side effects that happen in patients even if they're taking placebo. And so it's understandable. And so we follow the side effects. In phase II, we reported on some of the toxicities that were apparent. I would say if you look overall at the safety profile of our phase II study versus Nirogacestat's phase III, I don't see a lot of differentiation. I think they're close. And so we'll see what our phase III has.
I think something, the safety parameter that doctors have mentioned, I would say the most and asked about, and it's because of the population and the age and more women than men, they ask about something called ovarian dysfunction, which was reported in the nirogacestat trial. And so they ask us about it because of the age of the patients. And so I think that that's something that we'll see in our phase III. And our phase II showed that it was lower than Nirogacestat, but that was a small phase II. It was not a big phase III, so it's not fair. It's not statistically meaningful. So when we put out our phase III, I'd like to see, because I'm looking for that as well, I want to see how we have done on things like ovarian dysfunction, because I think that's an important one.
I think there are other ones, like some rash and things that you can manage well.
Got it. Got it. And then I guess if the data are positive, you potentially file for regulatory approval next year. What are plans to commercialize? Would you plan to commercialize yourselves, or would you seek a partner?
So our plans are to unblind the data within the next few weeks, report the top-line data. And then we have a great team that we're going to try to, as fast as possible, submit. My personal goal is to do it within four or five months, which is hustling. I've submitted and gotten approval for plenty of drugs, so I know the playbooks for doing it. The people that my colleagues that I'm so fortunate to work with at Immunome, a lot of them are from CGEN. Our Head of regulatory is from CGEN, our Chief Medical Officer, Head of Clinical Operations, Head of Commercial, Head of Manufacturing, on and on. They're all from CGEN. T hese are veterans that have gotten a lot of drugs approved and they're are not working on their first rodeo so to speak. I am incredibly proud to work with all of them.
And I know they're very serious and passionate about making drugs for cancer patients, and have made many. So we're going to get it done fast. We're going to submit, which is important to do fast, and do it in a very strong format, making it very simple for the FDA to review. And then we intend to launch the product. The head of commercial for Immunome is Rohan Shah. He was in charge of the Adcetris brand and the Tivdac brand. And he stayed on with Pfizer after the acquisition. Pfizer promoted him, gave him more brands, but I'm so fortunate to have him being the head of commercial for Immunome. And so he's launched drugs with me before, and he's a star. So we're well positioned there.
I would say, if you asked me that you have to tell me exactly how you're going to do it today, so you can't hold this to me forever, but what I would say is we will probably launch it in the U.S., Canada, and Europe. We'll probably use a distributor in what we call LATAM, which is Mexico, Central America, and South America. There are some great distributors that are Spanish-speaking sales forces that we would use for those territories. We probably use a distributor in what we call MENA, which is Middle East, North Africa. There are countries that, when I was launching drugs at CGEN, like Turkey, which are Western medicine, want the best medicines and other countries, and so MENA is an important market, and there are really good distributors there, and then in Asia, it's harder to use distributors. Not impossible, but harder.
And often in Asia, you work with partners that are Asian partners with boots on the ground already in Asia. So we have a plan to launch around the globe. Cancer patients don't know borders, boundaries, politics, colors, anything. Cancer patients know cancer. And my goal is to treat cancer patients around the world and get the drugs out there to the patients in need. So we have a plan to go and do it globally. Our phase III was global. It was U.S., Europe, Middle East, Asia. So we did that. It's purposeful because it's hard to launch drugs in different territories with having no clinical trials in territories. So we're positioned to be a global drug.
Great. And then beyond Varegacestat , you've got a portfolio of ADCs as well as a radioligand that's in early clinical development as well as preclinical development. IM1021, this is an ADC that targets ROR1. Talk a little bit about going after this ROR1 target. Clearly, you've got significant experience in the ADC arena over the last several decades. Why ROR1? And then I think recently the company had disclosed that in the phase I that you're starting to see objective responses in B-cell lymphoma. Maybe if you could share and provide additional color on that.
Sure. Thanks for the question. So I did not discover ADCs. These molecules existed for decades before I worked on them. They were primitive, is the way I would call them. And so I was working on antibodies. And this is about 30 years ago. I literally led a team to take apart ADCs and figure out how to make high-science versions of ADCs. And at the time, nobody was doing it like we were. And so we made the drug linker synthetic so you could scale it, use better antibodies, get better conjugation, and we came up with new technology. So let's just call it ADC 2.0. ADC 1.0 was all the pioneering ADC work. And so I would say what I led was not the discovery of ADC, but I brought, in a big way, ADCs to modern medicine. And so I'm very proud of that work.
It's led to many ADCs that I've launched and many. I mean, there's over 100 companies working on ADCs now. That might be an understatement. There's been a lot of different drugs approved and helping patients globally. I'm very proud of that work that I really led the charge of. What are we doing at Immunome? We're trying to develop ADC 3.0. There are issues and problems with ADC 2.0, which I'm a part of in a big way. For instance, ADC 2.0, and whether you're using an antimitotic, which was the bulk of what CGEN was doing, or a topo inhibitor, like what Daiichi was doing with DXD. T hese drugs are blocked by efflux pumps and resistance. We've developed an ADC technology that's outside of resistance for both antimitotics and topos. We don't get blocked by the resistance.
Resistance is a big deal. It can lower your response rate by 30% in patients that have the efflux pump, P-glycoprotein. That's one thing we've done. Another we've done is we've gotten rid of deconjugation. A lot of ADCs go in. They're in circulation. And a percentage of them, sometimes 10%, 15%, 20%, deconjugate. And then the drug linker will conjugate to something like albumin and cause toxicity. So our ADCs now, there's no deconjugation. Another thing that's really important is bystander activity. When you're in a lab and you take a mouse and you put a tumor on it, that is a homogeneous tumor. And I don't know any patients that I've worked on for decades that have homogeneous tumors. In humans, they're heterogeneous. So they're not like a mouse with a tumor on it. So bystander activity is important. So we develop permeability in the drug.
And we've tested it in exacting models, and it's great. And there's other things. So we have technology that, preclinically, we just presented it a month ago at the Triple Cancer Conference, is spectacular preclinically. I love it. Now the thing comes, you have to show that clinically. So we have our first ADC. We have seven named ADCs that are all in development, all in manufacturing to use this technology. And the first one out to shoot targets ROR1, which is largely for B-cell lymphoma. So we are developing the ROR1 ADC for two. There's two things to look at. One, is this a drug? And the second thing is, what does it say about our technology? Which is the same thing with Adcetris that CGEN was. It looked at the new technology and as a drug. And so we're in clinical trials doing dose escalation.
And we wanted to share a little bit of the excitement with this drug. So in our last quarter, we said that at multiple dose levels during phase I in escalation, we have seen objective responses. I am thrilled with the data we have so far. It's exceeded what my expectations were. I'm delighted with it. We need to present it at a right conference, and it needs to be presented by the doctors that are doing the trial. I know I said that before, but that has to be. But we gave a little insight into what we have seen. So I'm very pleased so far. And in 2026, we have three INDs planned and three for 2027. All six of those are for large, solid tumor markets. And we have an early one in 2026 for IND, mid 2026, late 2026, same with 2027.
So you'll see a regular pathway of INDs for big market opportunities that come with our technology. And I feel it already has shown me that it works and works well in humans.
With 1021, you've got the HC74 payload that you're using for the other six. You would potentially de-risk with that clinical data. I guess with 1021, Merck has a ROR1 ADC as well, but they use an MMAE Vedotin payload. Talk about the differences that you expect with the Immunome program versus the Merck program.
Right. So I'm very familiar with the Merck molecule. They bought it from Veloce Bio. I looked at it. I know the antibody. The antibody came from a small, now non-existing company. It wasn't a selected antibody. What we have is an antibody that was selected for high internalization. And if you want a great ADC, sometimes you have to sift through tens of thousands of antibodies looking for high internalization. People think antibodies bind to just a receptor, and that's it, and they're all the same. That is far from the truth. A receptor is like a big cup. Inside that receptor, there's thousands of dots. Those are epitopes. That's what the antibody binds to. It binds to something inside the receptor. And sometimes you'll find an antibody that will internalize, and some will not. And they're on the same receptor, but they're different epitopes.
So, you have to epitope-binding antibodies and figure out what they do. That's what I've been doing my whole career. And I have a very good hit rate of making drugs that's much better than the industry average because the teams that I work with always do very high science. And I think high science doesn't mean you will get drugs, but you have a much higher chance of getting them. So with all our cancer antibodies, we screen thousands and thousands of antibodies to find the ones that internalize better. The Merck one is modest internalization. I know it. I know that antibody. And then they use MMAE, which I know it well because I made it. And so it's not foreign to me. And so what we have preclinically blows the doors off of that. Now, we have to show that clinically.
Now, what they have shown in lymphoma is that at safe doses, 1.75 mcg per kg, they have roughly a 20% response rate. And then they go up to 2.5 mcg per kg, which is not a safe dose, too much heme tox, and they have a 40% response rate. But they can't use it. Now, in lymphoma, I've developed drugs. I launched a drug for T-cell lymphoma and Hodgkin lymphoma. If you come in and you say, "Hi, I have a drug that's got 25% response rate," my next sentence will be, "And we're closing the program." There's 15 of those, m ore. There's so many of those. You have to be differentiated. And what made Adcetris differentiated was 73% response rate in Hodgkin lymphoma and 87% response rate in T-cell lymphoma. That's why it was approved in phase II.
That's why all the docs wanted to use it in front line and combination, a pproved single agent and then combination. So our goal with ROR1 is to come back and say, "We have a differentiated product." Not that we have a 20%, 25% response rate product. We have a 50, 60%, 70% response rate product in patients that have failed three or more lines of therapy, which is what you get in early trials. Then that's differentiated. Then that's a real drug. So when you see data that we have to present, you have to see something that's differentiated and not 25%. Okay? That's where I think Merck is on their drug. They're 20% with a safe dose. So I know where the bogey is on that. But it's not just Merck. It's all the other drugs. And so we have to do a lot better.
And so we're up for the challenge. We're excited about it. We're in clinical trials, doing escalation, seeing what I think is really good data. But it's going to take time, and we have to grow their trials.
Great. I think we're about out of time, but looking forward to all the data updates imminently, I guess, with Varegacestat , as well as all the developments on the ADC pipeline in 2026, so I really want to thank you, Clay, for coming here, presenting, and sharing your insights.
Thanks.