Good afternoon, everyone. My name is Ted Tenthoff. I'm a senior biotech analyst at Piper Sandler, and before I begin our next presentation, I'm required to point out certain disclosures regarding the relationship between Piper and NextCure, which are posted at the back of the room and also at the registration desk. So NextCure is developing a rich, early-stage IO pipeline with multiple clinical updates coming. The company continues to invest in discovery and has come up with some really new, interesting preclinical programs as well. Here with us from NextCure is my good friend, Mike Richman. Mike, thanks for being with us.
Oh, thanks, Ted. Great to be here.
So your lead asset is NC410, which targets LAIR-2. Please tell us about this target and the phase 1 dose escalation data you've reported to date.
Great. Well, again, thanks for the opportunity to be here today. So our NC410 combo study is based on the earlier phase 1a study, where we looked at NC410 as a monotherapy approach in a phase 1a. So we looked at 41 patients, seven different dose cohorts, and about 10 different tumor types to identify a recommended phase 2 dose. The drug proved to be safe. There was no maximum tolerated dose, no DLT, no ADAs, and we saw about 20%-25% stable disease. So based on those phase 1a results that we reported on at SITC last year, we decided to proceed forward with the program. Quite interestingly, in parallel, we were doing a significant number of studies preclinically looking at combinations.
What we found out in three independent labs, NextCure, the University of Utrecht, and also at NCI, was that NC410 in combination with an anti-PD-1 or anti-PD-L1, showed significant synergistic effects. Because we had such a robust pipeline, we decided to forgo the monotherapy and move forward with the combination, and this is the subject of the phase 1b study currently ongoing, and that we'll be updating the Street on later this year.
Great. Have you reported any data on NC410 plus Keytruda yet, or will this be the first time we're getting data? And what cancer does it make sense to use that combination?
Yeah, excellent question. So yeah, so we'll be updating everybody pretty much on two different tumor types in the combination study. One will be colorectal and the other will be ovarian. We looked at four different dose cohorts based on the agency's recommendation. Since it was a combination, we had to start somewhat over, looking at 30 mg, 60 mg, 100 mg, and 200 mg doses. We're currently focused on the 100 mg and 200 mg doses. That's the dose range where we think we're most likely to see biological activity and responses. As part of the phase 1b, which still has a number of patients currently on study, we'll be updating the street on 25-30, perhaps a few more, patients by year-end.
As part of that update, we'll provide information on safety, which continues to look strong, clinical observations, and to the extent we have some of our biomarkers, we'll provide an update on that also.
Hopefully, next steps as well?
Hopefully, next steps.
Great.
We live for next steps in this industry.
Mike, sticking with the LAIR biology, how is LAIR-1 different? Maybe you can describe NC525.
Yeah. So LAIR-1 is a co-inhibitory molecule similar to PD-1, B7-H4, and other members in the class. And LAIR-1's overexpressed on T cells, and it binds collagen within the extracellular matrix of the tumor, and through this interaction, you get a negative signaling that shuts off the T cells through LAIR-1. Now, Mother Nature had something quite interesting through the evolutionary chain of events, where there was a LAIR-1 duplication in the gene. The lack of a better creativity, people call it LAIR-2. It's only found in non-human primates and humans, and it differs from LAIR-1 in two respects. One, it's soluble, and two, it binds collagen with higher affinity.
So LAIR-2, the subject of NC410, is a natural decoy that promotes the restoration of the immune system, and that's why in the case of NC410, we're adding more LAIR-2 as a fusion protein as part of the regimen with anti-PD-1. So getting back to your question, so why LAIR-1? So LAIR-1 is expressed on many different tumor types. Quite interestingly, you see it in solid tumors and liquid tumors. Predominantly, you see it highly expressed in leukemias and lymphomas. And we've decided to focus on AML, mainly because you can get an early clinical readout in looking at the reduction of blast counts. So what we're currently doing as part of the NC525 phase 1a study is we're looking at using anti-LAIR-1 in an AML patient population. We're currently in the fourth dose cohort and we've seen manageable safety.
We're looking obviously at clinical effects as it relates to looking at blast counts. We're measuring a number of different biomarkers. So what we'll be updating the street on later this year is where we are with the Phase 1a program, and as you mentioned earlier, next steps in advancing this program forward.
Great. You're also conducting P hase 1b study of your third clinical program, NC762, this one targeting B7-H4. Describe this target and maybe walk us through some of the preliminary data. I think you updated SITC last year as well, if I'm remembering correctly. Now, what could we expect from more data this year?
... Yeah, no, good memory. So yeah, last year at SITC, we updated on the phase 1a dose-escalation study. We looked at 18 patients, 5 different dose cohorts, in predominantly looking at ovarian cancer and breast cancer patients. B7-H4 is overexpressed in a lot of different solid tumors, predominantly in the gynecological space. So you see high levels of B7-H4 in ovarian cancer, breast cancer, endometrial cancers. As part of the phase 1b transition that we started earlier this year, we decided that we were going to select patients that had high levels of B7-H4 expression. We developed a clear, validated immunohistochemistry test, and upon consent, we were able to get biopsies from subjects, take those tissue samples, look at B7-H4 levels, and based on an established cutoff, we would enroll those patients and treat them.
So we're currently, again, moving forward through the phase 1b study right now. We'll update the street on some of those findings. Clinically, we're currently at the 20 mg dose, and then we'll report other findings, as part of that program moving forward. What's interesting is B7-H4 has become a very hot target in the ADC space.
Yeah.
So we entered into a partnership with LegoChem at the end of last year. It's a 50/50 co-development arrangement, where we've developed a next-generation B7-H4 antibody. Using the unique chemistry, payload, and linker system that LegoChem has developed, we now have a next-generation program. Because of the excitement of some of the data that others have reported at ESMO at the recent conference, people are starting to really pay attention to this target, and rightfully so. So we've decided to kind of move forward and initiate talks within the next couple of weeks, and with the goal of filing an IND for our B7-H4 ADC program. We actually have a new name for it, LNCB74. Beginning of next year, we'll be initiating manufacturing.
We'll be going through toxicology studies and then, following up with the IND filing later next year.
Great. That's exciting, and again, with the ImmunoGen/AbbVie news today, ADCs are a hot space again after a really good launch with Enhertu. So I love that you guys are still investing in discovery. You reported preclinical data on two new programs, very different, outside of oncology. You know, firstly, maybe you can just speak to how the FIND-IO platform, how your discovery capabilities really lead to these other target areas.
Yeah, great question. So, you know, from the start, we've always been very committed to discovery, and quite interestingly, we've identified a lot of novel targets through this effort. Many of them are on the back burner, but quite interestingly, as you mentioned, ADCs have become hot. And what we've seen out there, and somewhat unexpected, a lot of great chemistry, a lot of payloads, a lot of linkers, but people are looking for that next target beyond HER2, beyond EGFR, beyond even B7-H4, and now it's maybe CDH6. So, we're kind of perfectly placed because not all of our targets, but a good number of them, make very strong ADC candidates. And people have been very creative in the ADC field. They're even...
Someone just contacted us recently and said: "Can we put a payload on your LAIR antibody?" So I think people are starting to think differently.
Yeah..
I think it's gonna be a supply/demand issue, where the supply of chemistry is high, but demand for targets are gonna be great.
Mm-hmm.
So anyway, this discovery platform never stopped. It kinda has kinda waned over the years with respect to resource allocation, but we've identified a number of interesting targets that continue to have very strong biology and potential product products in them in the future.
Yeah. One of the first ones that I was surprised to hear about was anti-Siglec-15, which you had been developing for oncology, now with a novel role, NC605. Tell us a little bit about the preclinical data that you've seen, and you know, could this be a partnering opportunity?
Yes. Well, first of all, the NC605 program is a humanized monoclonal antibody targeting Siglec-15. And, Siglec-15, independent of the oncology application, this is a completely distinct antibody that binds a different region of Siglec-15. And Siglec-15 is expressed on osteoclasts. One can imagine these being a class of macrophages within what we call the BME, the bone microenvironment. And osteoclasts are important regulators of bone resorption. So what we've identified in a number of really exquisite preclinical animal models, working with some of the key thought leaders in bone growth, is we've established a data set where we've demonstrated that we could resorb bone, we could prevent... I'm sorry, we could prevent bone resorption, but more importantly, we could enhance bone formation. And this becomes really important when you start thinking about bone and fractures.
So we've been able to develop cortical bone, trabecular bone, but high-quality bone, and this becomes really important in the mineralization.
Sure
... of bone to prevent breakage. And so now that we've got this data set, we've decided to put this kind of on a path forward. We've developed a master cell bank. We've just produced tox material, and starting next year, we could start moving into defining the critical path and doing tox studies, and then moving into a clinical indication, an orphan indication called osteogenesis imperfecta, also known as brittle bone disease. This is an orphan indication that impacts young children and adults that unfortunately have an increase of bone fracture. There's also a lot of upside with respect to looking at osteoporosis, osteoarthritis. We've been talking to NASA, out of all places, out of this world, but, you know, two of the things they worry about in astronauts is radiation and loss of bone mass in a zero-gravity environment.
The military is very interested in enhancing wound healing and bone fractures.
True.
If you look at the increase in the geriatric population, just based on demographics, bone growth and bone fractures is gonna have a huge impact on patients.
Yeah.
And also, you know, healthcare costs. So from a partnering perspective, you know, not a lot of bone players. There are some folks that are developing some interesting molecules and making good progress in the bone space, but we think this opens up unique opportunities-
Yeah.
for creating partnerships in a number of different bone-related diseases.
Yeah, really cool. Such an interesting program, and I have only really begun to think about how broadly it could be applied, but that could be a lot of fun, and maybe you could do.... So, I mean, would you envision maybe taking the orphan disease forward yourself, or would this be something where you really would more likely partner the whole mechanism?
Yeah, we're pretty flexible on partnering just because of our portfolio of assets, but certainly an orphan indication for a young company. I think it's much more feasible-
Yeah
- to take it forward on your own. Other indications, like osteoporosis, would be much larger studies.
Yeah.
It would be a little more challenging.
Yep.
And then secondly, one of the things we're always faced with is really the globalization of clinical development. How do you develop the outreach from a-
Yeah
clinical and regulatory perspective? And I think a partnership from that perspective can be helpful.
Makes a lot of sense. You also recently presented preclinical data on an anti-APOE4 antibody, NC181, in Alzheimer's disease animal models. Tell us about this program.
Yeah, it's another exciting program, and it kind of fits in with this theme of kinda, you know, chronic diseases in the geriatric population. So, APOE is a key genetic marker in looking at Alzheimer's disease. We've been working very closely with Dave Holtzman from Washington University, one of the key opinion thought leaders in the Alzheimer's space. We've developed an antibody against APOE. We've defined in a number of different animal model settings where we could actually decrease amyloid plaque, prevent neural inflammation, and at least in the animals, we don't see the ARIA or the microhemorrhaging effects that a lot of the current neuro agents see in patient populations.
So we think this could be a very important game changer in treating Alzheimer's disease and preventing some of the side effects that people see with the current therapies.
How good are those animal models, and where would you envision kind of taking this next, or is this something where it's just kind of far enough outside of your area of expertise, or it might be an earlier partnership?
Yeah, I think we're looking at an earlier partnership-
Yeah
For this, just because it is a little outside our expertise. But however, you know, we see NextCure as a company focused on inflammation. So whether it's neural inflammation, whether it's inflammation in, you know, in a tumor environment or in a bone environment, but certainly, I think the skill sets and the patient populations. So yeah, we're very excited about talking with some of the key experts in this space. We've surrounded ourselves with a number of key opinion leaders that are providing us good guidance and advice, but I think a partnership would make sense in the future.
Great. And, you guys ended the third quarter with cash around $118 million. How long does this fund NextCure? What's it enable you to accomplish?
Yeah, so we have, yeah, $118 million as of the end of last quarter. It gives us a runway into mid-2025. So we won't be able to do everything, and to your point-
Yeah.
... you know, I think partnerships will become important. However, establishing partnerships in today's environment with so many companies has become more challenging, just because the bar for data content that, you know, partners want to see, has gotten much higher. So we're gonna have to make some key strategic decisions on what our priorities will be. They will be based on, obviously, data. They will be based on timelines, obviously, catalysts, and those programs that we pursue will continue to move forward, others we'll look to partner.
Yep.
Yeah.
Awesome. Great. Well, thank you very much, Mike. I'll just pause and see if there's any questions from the audience, but I think we covered everything pretty well. So thanks for being with us.
Great. Thanks, Ted. Really appreciate it.
Looking forward to an update by year-end.
Great. Thanks a lot for the opportunity.