Discussion with Clay Siegall, CEO of Immunome. My name is Michael Schmidt, Senior Biotech Analyst with Guggenheim, and I am really looking forward to this. Clay, welcome. Thanks for joining us.
Thanks for inviting me to your conference.
Clay, obviously, you have a lot going on at Immunome. You have varegacestat started from the FDA. You have an ADC pipeline and the radioligand therapy in the clinic as well. As you think about the next 12 months for the company, what are your key focus areas as you take the company into this next stage?
Clearly, varegacestat would come first. We have an action date or PDUFA date from FDA at the end of April in 2027. So we are excited to get that onto the market. We are well-prepared commercially, well-prepared manufacturing, and working hard at that. Also, over the next 12 months with varegacestat, we are working really hard with the European Medicines Agency. We submitted and got validated there, which is sort of like getting filed in the U.S., and they are equivalent.
We are working hard with the regulators in the U.S. and Europe. We are also doing the requisite meetings and clinical work we need to do in Japan. Also, we are working with potential commercial distributors, et cetera, in other territories. So we are looking at this as a global product and doing everything we can to get this to patients in need once we get approval.
That is going on. We also have a number of clinical trials that we are pursuing with varegacestat that we will talk more about in the coming times to see if we could broaden out our labels. So varegacestat represents something very important to us and our first commercial product.
Yeah, go ahead.
Okay. Over the next 12 months, I would say the one other big thing would be putting out a lot of clinical data on our many ADCs and really validating our new technology, which we think is state-of-the-art, one of the best, if not the best, ADC technologies out there, fixing many of the problems that were in ADCs over the last few decades, many of which I propagated. We would like to really do something dramatic and differentiated for patients with ADCs looking into the future. You will hear a lot of clinical data starting with ASH, which is next month.
On varegacestat, how is the product going to be positioned in the desmoid tumor market? Obviously, there is a similar drug already on the market. What are the key focus areas as you detail that product next year to physicians?
Mm-hmm. Our product, varegacestat, outperforms the current product on the market in every way you could look at the product. It has a higher response rate. It is once-a-day dosing. It is very effective on pain relief, as we detailed in our presentation. There are many different aspects of it. So it is a premier first-in-class product.
When you look at the incident patients, we think that our commercial team will be out there talking to doctors about using this as the first choice in the incident population. There is a prevalent population out there which is much larger than the incident population. The prevalent population is something that not all patients come in for therapy each year. The incident population is about 1,600 in the U.S. each year, about the same in the EMA.
When you look at the prevalent population, there is over 30,000 patients with desmoid in the U.S. Now, about 10,000, 11,000 of them come into therapy each year based on medical records, and they are looking for something. It is usually to combat pain, because they have pain, which pain is correlated with tumor growth. They want something. Over the years, docs have been giving them things like radiation or off-label drugs like SUTENT.
Only a few years ago, the very first drug ever approved for desmoid was nirogacestat. It gave another opportunity for patients. Our drug, we believe all the data is just so much better. It is such an improved therapeutic agent, largely because it has much better pharmacokinetics, and that is really the underlying reason why this drug is much better. So, we think that that is a great opportunity for all the incident and prevalent patients. We are going to go out there and try to do the best we can in representing patients and giving them opportunity to get the best possible outcome they can.
Yeah. Any learnings from the nirogacestat launch that you could implement or that you could leverage as you implement the launch next year? Talk about how launch-ready are you and how much more commercial build is necessary to support the launch next year?
Yeah. What I can say is, looking at a distance at what happened with nirogacestat, I do have to say it was a time where SpringWorks, there was rumors in the Wall Street Journal they were going to get acquired, and then ended up getting acquired months later. It is hard to launch a drug while you are in the middle of an acquisition. So, I will give them that there are logistical issues with that. So, that is one thing. We do not have that.
We are very focused on it. I think another thing is we are very focused on medical affairs and connecting with doctors. I have launched many drugs in my career, and medical affairs is critical to having a successful launch. We have the best medical affairs team that we can have. A lot of them came from Seagen, the leadership came from Seagen.
I have known them for a long, long period of time, and they did fantastic work and continue to. So I am very pleased with our ability to hit the ground running based on medical affairs. As far as the commercial team, our commercial leadership is Roee Shahar, and he launched two drugs at Seagen. He is a superstar commercial guy, and we are very well positioned to go forward with our commercial team.
Our head of manufacturing, Phil Tsai, also came from Seagen, where he literally made every product Seagen had, including the small molecule TUKYSA, which is, in a sense, similar because it is an oral drug to varegacestat, as well as all our ADCs. So I think we are, while we are a small company and we are only a little more than three years old, we are an extremely experienced company.
I think that launching a drug for us, for most small companies, is hard. I remember launching the first drug at Seagen, and you are a little bit like a deer in headlights when you do it. After launching many drugs now, we have a very strong playbook and experienced people. So I feel very confident we are going to get out there and get this medicine around to patients.
Okay. How big could varegacestat be in terms of peak sales potential?
We have not yet given sales guidance and everything. The price of nirogacestat, which is out there, is expensive. I think it is around $390,000 for a year of therapy. On our trial, the average patient was on for 20 months. It is an expensive drug. It is a rare disease drug. We have not priced our drug yet, but I am convinced based on interactions that we have had with payers that they understand the value that we have here and that the value is higher than nirogacestat.
Certainly, it is going to be a premium-priced drug, and we have not come out yet. For every drug I have ever launched, I have never talked about the price of the drug until after approval. I think that is bad karma. I think that also giving guidance on a drug before approval is also not appropriate yet.
You look at something where a price is $390,000, like nirogacestat, so how do you get to a billion-dollar drug? You could calculate how many patients you need. You need 2,500 patients or 3,000 patients to become a billion-dollar drug. Is that possible with 1,600 new patients that are treated for longer than a year and 11,000 of the 31,000 patients in the prevalence pool coming and looking for some therapy? Certainly, it is possible to have a really good market.
You have all Europe and the rest of the world. We are looking at this as a global drug, and we are not putting limits on it. I have seen all, you and other analysts, and there is a range of what analysts are thinking. We have not commented on it yet, but we are excited with the drug. We think it will really help patients.
Ex-U.S., would you anticipate launching yourself or would you partner the drug ex-U.S.?
That is a really good question. The very first drug at Seagen, I did partner. It was ADCETRIS, and I partnered that with Takeda. Takeda did a great job, and that drug became, a couple years ago, I remember U.S. was $1.2 billion and international Takeda's thing was $1 billion. It was a $2.2 billion drug. It certainly was good.
You look back at Seagen and that deal with the first drug, it brought in hundreds of millions of dollars upfront, hundreds of millions in milestones, and very strong royalties. It enabled Seagen to plow the money into other drugs. It became a $40 billion company. It is not a bad way to go, is to have for your first drug a partnership outside the U.S. I will tell you that there is certainly interest in varegacestat in many different ways.
But I also have a lot of experience launching drugs. My default position is keeping the drug and keeping our ADCs. There is a lot of interest in our ADCs as well, and not selling off assets yet, that is the default position. Of course, if there is really very productive deals, we will look at it and think about it. But it is not something we are going out pounding the pavement saying, "We have to do this or else we will not survive.
Okay. So maybe then shifting over to your ADC pipeline. First question is there are a lot of other ADC product candidates now being pursued by industry. You were obviously one of the original innovators in this space. But how do you construct your ADC portfolio? What is the concept behind target selection and then also payload technology that you are using at Immunome?
With ADCs, 30 years ago, I started working in ADCs, and at the time, there was only natural product drugs. So I wanted to solve a problem to make it much simpler to use, so I started to use synthetic drugs. Seagen was the first company to use synthetic drugs. Then you can make a drug linker unit that you manufacture and a conjugate with two pieces. In the past, it was three pieces. It was much easier, and we used enzyme-cleavable linkers. It was much safer and really ushered in the modern ADC. So now, what is the issue?
I looked at the field, and when we put together the Immunome company as it is known today, and said, "What is wrong with ADCs?" First of all, the two largest types of ADCs came from the Seagen, now Pfizer, ADC components and the Daiichi ADC components. Those two structures, if you will, have been used more than any other structure in ADC world. In fact, a lot of what people are doing now are just tweaks of those.
But both of them are susceptible to resistance. So that is something I wanted to It always bothered me. So we now have a payload that is outside of all the resistant mechanisms that we can test for. So that is a big advantage. Something else that is really important is permeability.
When you look at ADCs, you want something, your drug, because the antibodies bring it to receptor, you are getting inside the cell, and then you want your small molecule to be permeable. The reason why you want your payload to be permeable is due to something called bystander activity. I have been treating mice with tumors for decades, and you use a human cell line, and you have a homogeneous tumor.
I have been treating humans with tumors for decades, and they all have heterogeneous tumors, so it does not really match. What you need in a human, because they are heterogeneous, is you need to have the ability to, once it gets into a cell, you need it to also impact cells around it, and that is where permeability comes in. So we have our payload not only is outside of resistance, but it is very permeable.
That is two advantages. I could sit here talking for the next 20 minutes about all the other advantages we have, but I also want to talk about the antibody, because you asked about that. On the antibody, what is really important is to go after targets that have high expression in tumors and very low or minimal expression in normal tissues.
Since most tumor antigens emerged from normal antigens, it is really hard to find an antigen for tumors that has zero on normal cells. But what you try to do is try to find the minimum amount and not on tissues, like retina or things like that. So you try to find as best of a therapeutic window as you can. One of the things we do, which is really important, is we look for rapid internalization of an antibody.
A lot of companies that work with ADCs, they pick an antibody and they have it, and they just identify an antibody and they say, "Okay, we are going to use this to target X." We do not do it that way. We screen thousands and thousands of antibodies looking for the best internalizers. What makes that important is that when an antibody binds to the receptor, it is really not binding to the receptor. That is too generic. It is binding to an epitope within the receptor.
A receptor is like a big cup, and the epitopes are dots within the cup. That is actually what an antibody is binding to. So you could have an antibody binding to an epitope, and it does not internalize. Or you could have an antibody binding to an epitope, and it internalizes rapidly. Some of them signal, some of them do not signal.
That is why for years, people look at certain targets, they say, "Oh, well, that does not internalize," or, "That does not signal." Not necessarily true. You have to find different epitopes. So we are very professional and experienced at looking and selecting antibodies. Our head of antibody technologies came from Seagen and has a long history of picking out antibodies. So we have gone after some very exciting targets.
The other thing we are not doing with targets is we are not going after and becoming the 25th HER2, TROP2, Nectin-4, the ones that are out there. I do not fully understand why there are dozens of lookalike ADCs in development. It is really, really hard to take some of these ADCs and supplant them, and the trial size would have to be huge, and the years are huge. Instead, what we are doing is we are going after some very novel, exciting new targets.
The first one is for heme lymphomas, but the next seven are all for solid tumors. We have now, I think it is five drugs in clinical development right now. There is more INDs coming. We are really cranking forward hard. I would like to say that every one of our drugs is going to be a commercial success. It is never the case. My hit rate in my career has been very high compared to industry average. I think it will continue that way, but I also think that having multiple drugs that you are developing with great science is the way to win.
Yeah, great. Maybe diving into some of those a little deeper. Question on IM-1021, which is your ROR1 ADC, the first one really to have clinical data disclosures this year at ASH. We saw the abstracts recently. What does the early data tell you about IM-1021, and has it met your own bar to go into next steps?
Certainly, IM-1021, which targets ROR1, that is in trials, and it is in expanded trials. We are certainly investing in it, and we are doing a lot of work in it in lymphoma. When you start working with an ADC, it is complicated, and you have to be a little picky when you work with this. I have developed and gotten approved as many ADCs as anybody in the world, as you know. You have to start out, and you have to know what the dose and schedule are.
It is really important. I will give you just a quick little background story. ADCETRIS, used weekly, was very active, but had overlapping toxicity due to long half-life. The short story is ADCETRIS going to every third week became a $2 billion drug because it did not have overlapping heme tox and was very effective. Weekly, effective, but too toxic.
Every ADC has a very steep curve for response versus toxicity, because ADCs are potent directed antibodies. These are not drugs that have gigantic therapeutic windows. They just do not. Nobody's do. Whether it is ENHERTU or any of the ones I made, they have pretty narrow therapeutic windows. For drug developers like me, it is to find that therapeutic window. You look at ADCETRIS, and the next drug, PADCEV, we said, "Okay, let us start it. I am so smart.
We are going to start it every third week, just like ADCETRIS." That was wrong too, because the half-life was short. PADCEV, which started every third week, which was safe but not that effective, goes to weekly, and now it is a $3 billion drug. What you see is you have to first identify the dose and schedule. Now let us take this to 1021.
The very first in-human data come out, and we started it every third week, and we go out into the world, and we have a lot of responses. I think we reported of what we treated, 53% in the abstract responses. Keep in mind that our abstract was a data cut from June. It feels like a million years ago. It is a data cut from June.
You have to get the data and everything to put an abstract in by the beginning of August. At the conference, we are going to show a lot more data than what was in the data cut. I do not know exactly, but it could be double the number of patients, something like that. I do not know. In fact, the data cut for what is going to be presented at ASH was probably October. We continue to treat patients.
Just because there is a conference does not mean you are stopping or anything. We have a program, and the most important thing is to collect the data and work with FDA, work with doctors and patients. I think what we have is a very active drug. When you look at lymphoma in third line plus, which is what we are doing, patients have had a RITUXAN chemo regimen, patients have had CAR T-cell engagers. I mean, these are heavily pre-treated patients.
Once they are in third line plus, there is not really good choices. There is a bunch of different choices that will give you 20% to 30% response rate. A lot of them have toxicity. What we need to do is not come up with another drug that has 28% response rate. That, to me, would be something we would announce that we are closing the program.
What we need is something differentiated, and we need 50%, 60%, 70% response rate. We need outpatient therapy, because as you know, a lot of the T-cell engagers, you have to go into the hospital to get them, and because of CLS or CRS, whatever you want to call it. We want outpatient therapy.
We want it to be a ubiquitous drug for B-cell lymphoma so that you do not even have to screen for it, and we want something that has a differentiated response rate of 50%, 60%, 70%, so that in third line plus, it will be drug of choice, and you could go and quickly get an approval in third line plus, which is exactly what I did with ADCETRIS first.
I moved that into earlier lines, and when you have a really good outpatient drug with a differentiated response rate, doctors are very excited about bringing it early and combining it with drugs. That is the way to make this into an initial approval into a much bigger market opportunity and help patients. We are cranking along. Our first report on this shows, if you look at all doses and everything we looked at, over 50% response rate.
But what is not in there is saying, "Well, what is the right dose and schedule? Could we take what we learned from our initial studies and improve it? Could we go to 53% and make that our bottom line? What could we do to get up to 60%, 70%? How do you do that?" That is what we are working on now.
There'll be more presented at the conference, and we are still working really hard on it. I'm excited with IM-1021, the ROR1 drug. I'm not here yet saying we're ready to get it approved tomorrow, but I don't like wasting money and time on drugs. I'm still very excited about it.
How close to finding RP2D are you at this point?
That's something that we're going to be presenting data at the conference. I don't feel comfortable talking about whether we've fully selected our recommended phase II dose yet or not. It's coming in a few weeks. It's ASH in three or four weeks.
Correct.
We'll present a lot more data, and we'll continue to crank forward. That's something keenly in our mind. One of the goals here is to try to do a single-arm, single-agent approval pathway in third line plus. That's exactly how ADCETRIS and PADCEV were approved, for instance. You have to do that based on differentiated activity in a disease setting that's late line and there's not a lot of really good alternatives.
To do that, to get the FDA to say, "Yeah, that's something we'll review," you need to bring forward differentiated data. You can't bring forward something that's the same as everyone else. Then they'll say, "No, you'll have to do a big, giant randomized study," and all that. That's our goal, is to get differentiated data, outpatient therapy to really help patients.
In your opinion, what is the efficacy bar for an accelerated approval these days in late-line DLBCL, and how important are CRs as opposed to ORR?
Yeah. First of all, I don't know. There's not a written document from FDA saying, "Here's the bar." I would say it's And it's complicated when you look at it. The CRs is you need to have some CR rate. It's not 100%, but you need to have some 20%, 30% CRs, in my opinion. Not in pancreatic cancer, like you just heard from RevMed, but in lymphoma, you need to have some CRs.
I don't know the exact rate. If you look at a waterfall plot and you have a 50% response rate, but every single patient is below the line, and so you have 50% having reducing disease and 50% having a response rate, that means 100% of the patients have tumor shrinkage. That's a good 50% response rate.
You could have a 60% response rate, and the other 40 is above the line, and they're growing. That's not a very good 60% response rate, is it? Having a set number is not really, in my experience of decades with the FDA, they look at the whole data. They look at the dataset and say, "What happens to the patients that respond? How long is the duration?
What about the patients that don't respond? Are their tumors shrinking? How long is that duration? Is this safe for outpatient therapy?" You have to have all of the pieces and not just, "What is your response rate?" and not see the rest, because duration and other parts of this are very important.
Great. We didn't get to talk about the rest of the pipeline. Let me ask you one before we wrap up. How important is this ASH ROR1 data in terms of validating the rest of the pipeline?
I think every piece of data is important. Some folks have said, "Gee, if your data in lymphoma is really good, that means your solid tumors will work." Some people said, "Well, if it's not good, then your solid tumors won't work." I think that's a little bit overreaching.
Okay, great. Well, I think let's wrap up here, but looking forward to ASH then for these important updates and
Thank you.
we're looking forward to talking to you then. Thank you, Clay.
Thanks.