Hi everyone, thanks for joining us at the H.C. Wainwright 27th Annual Global Investment Conference. My name is Emily Bodner, and I'm an Equity Research Analyst at H.C. Wainwright. I'm pleased to introduce Michael Richman, who's President and Chief Executive Officer of NextCure. For anyone newer to the NextCure story, can you walk us through your key pipeline assets and some of the latest work you've been doing this year?
Great, thanks Emily, and thanks for including NextCure in this year's H.C. Wainwright conference. NextCure is about a 10-year-old biotechnology company located in the Mid-Atlantic region, focused on really two key pipeline assets. Both are antibody-drug conjugates in the oncology space, and both focused on predominantly women's health and other tumor indications that we're pursuing. Our first program is a B7H4 antibody-drug conjugate using a proprietary linker system in collaboration with our partner LigaChemBio, where we have a 50/50 co-development arrangement that's currently in phase one. That program will have initial proof-of-concept readouts in the first half of next year. In parallel, at a similar stage of development, is a new in-licensed opportunity.
This is a CDH6 antibody-drug conjugate using a topoisomerase inhibitor, and this evolved through a recent partnership and in-licensing arrangement from Simcere Zaiming in China, currently also in phase one clinical development with a clinical readout in the first half of next year. That's our pipeline. There's a lot of similarities with respect to the antibody-drug conjugate technology, both within the ovarian, breast cancer, endometrial cancer space, and both with similar stages of development.
Great, maybe starting with your lead asset, LNCB74, which is your B7H4 ADC, can you walk us through the excitement around this asset, the evidence that we have so far of B7H4 in solid tumors, and what makes it an attractive target?
Yeah, we're really excited about this target, which is a good thing. Unfortunately, there's a lot of other companies equally excited, so it's a fairly competitive space. We've been in the B7H4 space for a long time based on some initial work we had done in the immuno-oncology space. This is a target that's overexpressed on a number of tumor types, predominantly in ovarian cancer, endometrial cancer, fallopian tube, breast cancer, and other types too. We've been working over the years to develop candidates that would target B7H4 because of its overexpression profile on these various cancers. We had originally taken in a naked antibody into the clinic, which unfortunately did not work, which hence made our transition into the antibody-drug conjugate space and entering into this partnership with LigaChemBio to co-develop the B7H4 ADC.
It's got a unique construct, which I think differentiates us from what others are doing, specifically with respect to the linker system. This involves a beta-glucuronidase linker, which is really the only B7H4 ADC currently using that. This was developed again in collaboration with LigaChemBio and gives you much greater specificity to target the tumor through the B7H4 expression profile, and also to avoid a lot of the toxicities that one sees in looking at these various payloads. Using the glucuronidase system, we avoid a lot of the off-target toxicity in order to get the ADC specifically into the tumor where the beta-glucuronidase cleaves the payload and hopefully kills the tumor.
Great, maybe going back to your point a bit about the competition, obviously there's several B7H4 ADCs in development. We have AstraZeneca's PSAM, which had very positive data recently, also Pfizer, who recently discontinued development of their B7H4 ADC. What are your views of these different programs? Based on the construct of your ADC, do you think you could potentially have better efficacy and/or safety from the other competitors?
Yeah, that's a great question. There are a number of players, big and small, in the B7H4 ADC space, and each one varies differently. While they all have antibodies that target B7H4, the linker systems are different and the payloads are different. Some have tubulin inhibitors like the one we're developing, others are using topoisomerase inhibitors. With the various payloads, you have different toxicity profiles that one sees in these various patient populations. Also, the regimens or the scheduling and how we administer these ADCs in these different subjects differ.
I think from a differentiation perspective, some of the advantages that we've pursued is we have a high affinity antibody, it's well internalized, we have a unique linker system, as I described, with beta-glucuronidase, and it's got a little bit of a different payload since it's a tubulin inhibitor, which differs from what AstraZeneca and what some of the other groups are doing with topo inhibitors.
Great, how commonly expressed on some of these key solid tumors like ovarian and endometrial cancer is B7H4, and how has that kind of informed on your phase one strategy?
Yeah, that's a great question. B7H4 in particular is overexpressed on many of these different gynecological tumors. The challenge is the various spectrum and different expression profiles, and what we try to do to differentiate ourselves from others and to increase the overall response rate of these patient populations is we use an immunohistochemistry test to select patients that have the highest level of B7H4. When we screen subjects in the clinical trials currently in phase one, we'll take a biopsy, we'll use a CLIA-validated immunohistochemistry test where we can then look at the various B7H4 expression levels, and then based on specific designated cutoffs, we'll take those high expressors, which we think will be most responsive. Other companies are doing things similarly, but each test is different from the standpoint of sensitivity.
Each biopsy sample varies, so we always try to get a quality tumor sample from an individual so that we can maximize the accuracy of the B7H4 expression level before we enter those patients into the study.
Great, can you walk us through a bit about where you are currently in dose escalation in the phase one trial, and what kind of endpoints and key metrics you're looking at in the trial?
Yeah, so we're always looking at safety and overall response rates. We're currently in our fourth and highest dose cohort in the phase one dose escalation. We have not seen any DLTs. Safety has been very tolerable. Our goal now is to start what we call backfilling into patient populations that will be selected for B7H4 high and that we think will be most responsive. What our plan is now is to kind of lock in a dose based on pharmacokinetic data that we're currently calculating in this patient cohort and then move forward with some of these backfills, predominantly in ovarian and endometrial cancers, and then hopefully maximize a response rate that will justify moving into a phase two.
Okay, how many patients in total are you expecting to have data on, and when are you kind of planning to share initial phase one data?
Yeah, you know, we'll probably have an update before year-end, but when it comes to specific data, it will probably be our guidance is in the first half of 2026. We haven't disclosed a number of patients. Obviously, we want to maximize the data set to give us some clarity on the response rates that we hope to achieve. Also, when you're selecting patients, not every patient qualifies for the study, so there's kind of a drop-off rate on some of those B7H4 low individuals and selecting for the high patients.
How are you currently thinking about what would be considered a positive response rate, obviously in different indications? We've seen a lot of breast cancer data, now we've seen some endometrial data, what might that look like for you?
Yeah, the good thing about having competition is it gives you kind of a lens into what others are observing in various patient populations with similar constructs. What we've seen historically with some of the companies you mentioned is pretty much a 20% to 25% overall response rate. If we're looking at non-inferiority, we would want to achieve at a minimum a 25% response rate. If we're looking for superiority, we would like to see something obviously much greater than that from an efficacy perspective. From a safety perspective, obviously, we'd like to see clean safety. Unfortunately, in the antibody-drug conjugate space, you're dealing with payloads that are chemotherapeutic agents.
They are toxic, but so far, based on the linker system we've used, we haven't seen any DLT, which gives us some optimism that we'll be able to prevail on safety and we could focus on the right patient population to look for that hopefully maybe greater than 25% or 30% response rate.
Maybe shifting gears to your CDH6 ADC, which you recently announced that you've licensed in the U.S. What attracted you to this particular asset, and what were the terms of the transaction with Simcere Zaiming?
Yeah, so we did a worldwide, entered into a worldwide exclusive license, but for China with Simcere Zaiming. Zaiming is their ADC part of the business, and this entails a CDH6 antibody-drug conjugate. Unlike our B7H4 payload, which is a tubulin inhibitor, the CDH6 ADC is a topoisomerase inhibitor, and this is a proprietary topoisomerase inhibitor that's been developed and tested at Simcere Zaiming. The reason we liked it is, you know, when you're a small company and you're going to make a big investment and take on, you know, manageable risk is we wanted to go into an area that we were comfortable with. With the B7H4 ADC program, staying with the same modality of having another antibody-drug conjugate made a lot of sense. Knowing that CDH6 is overexpressed on ovarian cancer and endometrial cancer, it gave us synergies with respect to what we were doing with B7H4.
We knew the sites, we knew the investigators, we know that patient population really well. There were a lot of benefits. Also, from a commercial perspective and trying to differentiate one ADC versus another, B7H4 and CDH6 are co-expressed on ovarian cancer patients, which is quite meaningful because now this gives you the ability to potentially look at a combination of two distinct targets that have both been validated clinically with two distinct and different payloads. Our goal in NextCure, and I'm sure with many of the ADC companies, is really the kind of the fight we have in dealing with tumor resistance. You see a lot of tumor resistance, and hence limiting the durability of responses in the patients that we treat with these antibody-drug conjugates.
Now having a CDH6 ADC with a topoisomerase payload and a B7H4 with a tubulin payload gives us the ability to treat patients either in combination or even sequencing them. What do we mean by that? Sequencing would be you would look at a biopsy of an individual, you would look at their B7H4 expression, you'd look at their CDH6 expression, and then determine whether or not you want to basically hit the patient hard with both drugs or start with one and then follow with another. That's why we're really excited. It just fit perfectly. We look at opportunities all the time. Just like many companies, we've been hanging around China, and the data coming out of China has been really impressive.
You know, having been in the business for 40 years, I haven't seen such impressive data packages and how information is organized and how these programs are being generated. The reason we like the program so much is, while we'll soon be dosing patients here in the U.S., our partner, Simcere Zaiming, is dosing patients in parallel in China. This gives us the ability to almost double the enrollment rate and to have patients both in China and the U.S. receiving this drug. The second part of your question was the terms. It was expensive for a small company. We paid $12 million upfront. Obviously, this gave us worldwide exclusive rights, but for China, they're participating in financing their own clinical development in China, and we get to share and exchange this data.
Another part of the program is they're supplying drugs free of charge for us to embark on the phase one in the U.S. shortly. They also made a $2 million equity investment in the company. I think this shows the long-term commitment of having a partner that you're not only co-developing a product, but also that they're interested in the growth and well-being of NextCure itself. One thing that we haven't really kind of talked much about is we also have exclusive rights to their topoisomerase inhibitor technology for another target that we have in NextCure that we have not disclosed yet. It shows that we're working on multiple fronts with Simcere Zaiming, and we're very excited about starting this clinical trial here in the U.S. shortly.
Great, how does CDH6, I guess, differ from B7H4 in the tumor types you mentioned, like ovarian and endometrial? Obviously, you said it was co-expressed, so what does that overlap kind of look like from estimates we have so far, and what's some of the emerging data that we've seen from competitor CDH6 ADCs?
Great question. You see about 45% to 50% of at least ovarian cancer patients that both express B7H4 and CDH6. In some cases, it's higher, depending on what those biopsy and those immunohistochemistry cutoffs look like. I think we could comfortably say that depending on whether you're looking at high or low expressors, and whether you're looking at B7H4 or CDH6, it gives you the ability to use both of these programs in parallel.
Also, kind of going along the phase one trial that Simcere Zaiming is running, what does the trial design of that study look like? Obviously, you've announced that there's a partial response, so maybe just provide a bit more detail and any timelines for more data.
Sure, sure. I didn't answer the other part of your question regarding other competitors also. There were two other CDH6 players, Daiichi Sankyo, where they've seen a 46% response rate with a CDH6 ADC, and then a more junior company, private company Oncust, has seen equally good responses, around 36% in their CDH6 ADC. It's a very validated target. To your question on the phase one clinical trial, we're currently in dose escalation. All the patients have been enrolled in China. Simcere Zaiming had the insight of filing the IND here in the U.S. That IND has now been transferred to NextCure. We've already engaged our clinical research organization. We're signing contracts as we speak with the sites, many of which are already involved and engaged in the B7H4 program. We'll be starting probably by the end of this quarter of enrolling patients in the U.S.
We'll most likely be starting a cohort behind what Simcere Zaiming is doing in China, just to kind of, you know, they'll be at the cutting edge of trying to determine what that DLT might look like, which they have not hit today.
Okay, how are you kind of thinking about design for the U.S. trial? Are you kind of looking at similar indications to what Simcere Zaiming is looking at, or are there certain indications in particular you'd like to focus on or planning all comers?
Yeah, we're driven by the expression profile of CDH6. Predominantly, we're looking at ovarian and endometrial cancer. CDH6 is also expressed in kidney cancers, and some of those subjects are currently being enrolled in China. Quite interestingly, looking at the non-small cell lung cancer patient population, in particular looking at the EGF receptor wild type segment, those subjects seem to also overexpress CDH6. We've developed, or Simcere Zaiming has developed, the assay that's currently being transferred to the U.S., an immunohistochemistry test that will enable us to look at non-small cell lung cancer biopsies and select those individuals that are CDH6 positive. Moving forward beyond those tumor types, we'll also be looking at other smaller tumor types that express CDH6.
Great, you mentioned a bit earlier about potentially sequencing or combining the ADCs. How can you kind of go about figuring out the best strategy to do this, and is this something you're currently looking at preclinically?
Yeah, so I'm going to use ChatGPT to determine the regimen. No, but seriously, it's a great question. We're breeding animals right now. These are AVCAR, so these are ovarian cancer mice that express ovarian cancer tumors, and we know this model works. We've used it historically, and we're in the process of breeding those mice and then looking at, since they express both targets, we'll then be able to algorithmically and experimentally test the combinations of the B7H4 ADC conjugates together, and then we can also sequence them. We can look at different doses, which will enable us to calibrate the regimen moving forward. This is what we're really excited about because, you know, there's a lot of ADCs out there, and the question always comes, how are you differentiating?
You can only differentiate through one of three parts, you know, the antibody itself, and those are all high affinity, highly specific molecules. The linkers vary, and they may give you some benefit, and then you're in one of two classes of payloads. I think when ADCs start coming out, you're going to start seeing combination therapies and what we believe sequencing approaches to best conquer tumor resistance.
Great, and you mentioned that Simcere Zaiming is also providing you tech for their topo inhibitor. Are there any other targets that you find interesting or that you might look to advance?
Yeah, coming historically from an IO perspective, we have a lot of targets. We're rich in targets, and we plan on, obviously, we don't have the ability to move them all forward, but there's like three or four that have been prioritized, one that we'll work closely with Simcere Zaiming. Each of these targets has different expression profiles, different tumor types. Depending on which target we're looking at, based on the biology, the mechanism of action, the expression profile, you'll be hearing a lot more of those in the years to come.
Great, maybe to close out, if you could just summarize for us some of your upcoming catalysts and milestones for the next year or so.
Yeah, two big catalysts, two phase one clinical proof-of-concept outcomes in the first half of next year. We've got more than enough financial means to see both these trials through, and we're keeping our fingers crossed. Obviously, we're very optimistic just because of what others have already shown in validating these targets. Our goal is to kind of preserve and perhaps improve on safety versus what some of the other competitors are doing, and then hopefully kind of be superior from an overall efficacy perspective.
Great, perfect. Thank you very much, Michael. Thanks everyone here for listening in.
Thank you.