Ladies and gentlemen, the program is about to begin. Reminder that you can submit questions at any time via the Ask Questions tab on the webcast page. At this time, it is my pleasure to turn the program over to your host, Alec Stranahan.
Hello, everyone. Welcome to the end of day two of the 2022 Bank of America Healthcare Conference. Thanks for joining the session with NextCure. My name is Alec Stranahan. I am Vice President and Senior Biotech Analyst covering NextCure here at B ofA . I'm pleased to be joined by Michael Richman, President and Chief Executive Officer of NextCure. Michael, thanks for joining.
Thank you, Alec. Great to be here. Thanks for including us in this year's conference.
Great. Great. I believe Michael is going to run through some prepared remarks to start, but then we will jump into the Q&A after that. Michael, over to you.
Great. Thanks, Alec. Yeah, I thought it would be helpful just to include some opening remarks on NextCure and kind of where we've been, but more importantly, where we're going. We've been at this for about six and a half years. We're located in Beltsville, Maryland, and we're focused on next-generation immunomedicines, in particular, looking in the oncology space. Happy to say that we now have three clinical candidates, novel first-in-class proprietary programs that will all have readouts in 2023. Our fully integrated organization that includes a GMP manufacturing, extensive network of biomarker tools, and the ability to develop tests to select patients are now being utilized in each of those three clinical trials, which will have readouts next year in 2023. We're really excited about telling you about our first program, NC410.
This completed phase I. We reported those updates at SITC, and we'll be, we've already started enrolling in the phase Ib/II. Our second program in the pipeline is NC762. This is an anti-B7-H4 program. Also at SITC, completed, provided an update on the phase I clinical trial and have already started enrolling in the expansion phase and will also provide an update towards the end of next year on that program. Finally, our third clinical program that we recently announced, NC525, we filed the IND in October. We're fortunate to get the 30-day clearance from the FDA, and we'll start enrolling patients beginning of next year. Looking forward to telling you a little bit more about each of those three programs.
Independent of our fully integrated organization and three clinical candidates, we also have a very strong balance sheet of $169 million as of the end of last quarter, which provides us a runway into mid-2025 and more than ample resources to advance each of our three programs. Happy to take your questions today, Alec.
Great. Thanks, Michael. Now we'll jump into the fireside portion. I've got a few here, but for those on the line, if you do have a question, feel free to send them over through the Vericast platform, and I'll read them off anonymously as we go along. Michael, maybe, you know, I wanna get to the active pipeline because obviously that's where the action's gonna be, but maybe just to start up front, you recently made the tough choice of discontinuing development of NC318, which you acquired, I guess, through Yale. You know, that must have been a difficult decision. If you could just walk us through your thought process here, given the data and, you know, your priorities looking forward.
Yeah, great. Thanks for bringing that up. You know, even though we've been at this for 6.5 years, it feels like we have a very long history. NC318, which was our lead program, certainly, was a big part of the company, you know, for the last, since, its conception. Very difficult decision to make. Obviously, I wanna thank the investigators and the patients for participating in this study.
With that said, recently we came to the conclusion that the inability to reproduce some of the earlier clinical observations that we had in the phase I and II trial regarding some of the clinical responses we had seen in lung cancer and a fair number of stable diseases, we came to the conclusion that we could not reproduce some of the earlier findings in a monotherapy setting. We actually did a lot of modifications along the way with respect to narrowing down the tumor types, increasing the dose, increasing the frequency, administering patient selection. Even after dosing over 100 patients, we had to make that difficult decision.
With that said, we still believe in the target, we're still supporting our colleagues at Yale University who are conducting a combination study of NC318 with Pembro, where Merck is kindly providing the drug to support that study. We stay very engaged collaboratively with the Yale team. The focus right now has been strictly on lung cancer patients, mainly in PD-1 refractory subjects where we continue now looking at NC318 in combination with Pembro, an amendment is currently being made to increase that dose to 800 mg.
Great. Maybe we could talk a little bit more about the Yale study, in terms of, you know, patient selection. I know you guys have your S15 assay, that you were implementing. Is this also a part of the Yale study as well in terms of enrolling patients?
Currently Yale is looking at PD-1 refractory patients in lung cancer. They are taking biopsies, but they'll be looking at S15 expression retrospectively. With that said, there's also a number of key biomarkers that they'll be looking at in that setting with respect to looking at tissue samples and blood samples to, you know, get, you know, further understanding of how the drug is behaving mechanistically. What impact, if any, you know, the anti-PD-1 drug is also having on the utility of NC318.
Okay, great. Well, definitely looking forward to the update from the investigators at a later point. Maybe we can shift over to the active pipeline. Maybe first NC410. We saw data at SITC recently, like you mentioned, but maybe just at a high level, could you maybe talk a little bit about the novelty of LAIR1 as a target? I know in your preclinical work, you know, you've showed that the utility of LAIR1, and pretty broad expression, you know, both, you know, could lead to responses in mono therapy, but also, you know, could lend itself to CTI combinations as well. Maybe you can just talk about, you know, that target, you know, and what gets you excited about it.
Well, first of all, I am very excited about LAIR1. We've been working on it for five years. It's a fascinating pathway and mother nature has really challenged us to really understand how best to understand the pathway, but more importantly, how we navigate drug development. I'll tell you a little bit about the biology and then walk you through kind of two unique novel candidates that we're developing, intervening through the LAIR1 mechanism. First LAIR1, co-inhibitory molecule like PD-1, is expressed on T cells and other myeloid cells. Quite interestingly, it binds one of two binding partners, C1q, which is part of the complement pathway. I think more interesting, collagen, which is part of the extracellular matrix we call the ECM, not your equity capital markets.
What we've learned over the years is that collagen is a key resistant factor in why a lot of anti-cancer therapies are unable to kill the tumor and restore immune function. What LAIR1 does is when it binds collagen, there's a negative signaling through the T cells and turns it off. What quite interestingly, only in humans and higher primates, there was a gene duplication somewhere along the evolutionary chain. We call it LAIR2. LAIR2 differs in LAIR1. It's 70% homologous, but it's soluble, and quite interestingly, it binds collagen with greater affinity. Basically, it's a natural decoy to outcompete the negative signaling through LAIR1 to restore immune function. We're not that smart. We just follow what mother nature has already taught us.
What we realized early on, that in looking at LAIR2, knowing that it was good for the system, we thought, Well, why don't we just add more LAIR2? We created a biomimic, we call NC410. It's basically a combination of two forms of LAIR2, and it outcompetes the binding of LAIR1. NC410 has a pretty extensive preclinical technology package. We've been through the phase I that we reported at SITC that you mentioned, Alec. We dosed 40 patients. We looked at about seven different dose cohorts, 10 different tumor types. The outcome of that phase I study gave us confidence that we were able to see very good safety, good PK.
We looked at an extensive assessment of biomarkers, that demonstrated some mechanistic activities in binding the C1q, remodeling collagen, and also looking at some other biomarkers related to our T-cell activation. Based on that data, and certainly it laid the groundwork for moving forward, advancing that program forward. In summary, NC410 is a LAIR2 biomimic. It remodels collagen within the tumor, and through that remodeling, you actually change the architecture of the tumor. Imagine punching holes in the tumor itself, which now enables the T-cells to infiltrate, to kill the tumor, and to restore immune function. This is one of the reasons we're so excited about NC410, because it's a completely different way of looking at antitumor responses. We know that high density collagen creates this resistant barrier.
In fact, many of the tumor types that are very collagenous are resistant to PD-1 therapy. We think NC410 creates a unique opportunity to look at various combinations moving forward, where we can look at the tumor side and then also looking at the infiltration and impact of various immune cells within the tumor microenvironment.
Great. It sounds like there's some clear, you know, biologic rationale for this being a backbone for combos.
Yeah, definitely the backbone as well as a wishbone and a funny bone.
Maybe we could talk about the clinical progress. We saw an update on the study design for the combo at SITC. You know, could you maybe walk us through this presentation and any unique considerations for this study, and maybe how you've incorporated any lessons from your prior studies with other assets?
Really good question. Our preclinical work always entails looking at evaluating a number of different combinations. What we saw early on was significant synergy in tumor killing in a number of different animal models when NC410 was combined with an anti-PD-1 or anti-PD-L1. This particular data set was highly reproducible in three independent labs, and we published on it in a number of journals last year. We, as well as Jeff Schlom's group at NCI, as well as Linde Meyaard's group at the University of Utrecht in the Netherlands, each conducted combination studies where NC410 and anti-PD-1 combos were highly synergistic. It was that data set that really laid the groundwork for making the decision to move forward with NC410 combined with pembro. Merck was kind enough also to provide the drug to support this study.
The reason we're so excited is, we've started to look at things a little bit differently, Alec. You know, we realized that people that study tumor biology are sometimes a little different than people that study immunology. Immunology people are focused on the various immune cells within the tumor microenvironment. People that study tumor biology actually study the structure of the tumor, the collagen, the fibronectin, different pro-proteins that expressed on the tumor in what we call the extracellular matrix. What we've been doing at NextCure now is through the unique understanding of the mechanistic activities of what goes into a tumor mass, how it metastasizes, and how we need to align that understanding with what's happening in the tumor microenvironment makes the NC410 pembro a perfect combination.
NC410 breaking up the tumor mass, we could actually measure collagen degradation products we call CDPs in patient serum, and aligning that with an anti-PD-1, where you can activate the T cells now to come in and to attack it.
Got it. Got it. The phase IA monotherapy dose escalation is now complete. I think, you said that the, you know, the profile is, you know, safe, well-tolerated, you know, everything you'd want for a combo partner. Could you maybe talk a little bit more about the decision to move straight to combo from here?
Yeah. Well, the main reason was really based on the impressive preclinical findings, as I mentioned, you know, in the highly reproducible synergistic effects we saw on multiple models in three independent labs. With that said, also, I think in all honesty, the microenvironment or the macroeconomic environment really has kind of really forced us to, you know, prioritize certain approaches. Knowing that the combination therapy will most likely be the best commercial and clinical opportunity moving forward, we decided to move that forward, similarly to what we did with NC318. I think in the old days, we looked at monotherapy and then over time advanced into a combination setting.
Knowing how expensive it is to run clinical trials these days, the challenges in enrolling patients, we thought that we would take the strategic focus on looking at the combination approaches, and it's really well supported by all the preclinical validation work our scientists have done.
Great. In terms of next steps, you know, do you have any sort of frame for us to think through, you know, timing on potential data from the combo study? Is it, you know, next six, 12 months or maybe more 2020, 2024 storefront?
No, we don't go too far out there. Yeah, we're looking at probably, yeah, definitely the next six to 12 months. We've already started dosing patients in the combo. We're looking at both a PD-1 refractory basket arm of patients. In particular, we're looking at colorectal, esophageal, endometrial, head and neck, and ovarian. Those five tumor types are fairly collagenous, so it fits well with the mechanistic approach we're taking. Also, we have another arm where we're looking at more of a naive setting in looking at both colorectal and ovarian cancer patients. In the colorectal setting, we're actually looking at MSS and MSI-L. Those individuals which make up the largest segment of colorectal cancer patients sadly have not responded to an anti-PD-1 therapy.
We, along with, you know, others working in the PD-1 space, hope that NC410 will have the opportunity of, kind of changing that paradigm and improving clinical responses for the colorectal cancer as well as the other tumor types in patients we're looking at.
Great. Definitely looking forward to that update. Maybe switching gears now to NC 762. This was another one we saw some initial data from at SITC. You know, could you sort of walk us through the presentation, you know, the NK response, duration of treatment, and how this sort of adds conviction in your mind as the study continues to dose escalate?
We love B7-H4. Fascinating target. Another co-inhibitory molecule, overexpressed on many different tumor types. NC762 is a humanized monoclonal antibody targeting B7H4. Our focus has been predominantly in a number of major tumor types such as ovarian, breast, and lung. You see B7H4 overexpressed in many of the gynecological cancers. As you mentioned at SITC, we reported the completion of the phase I dose escalation, safety, and tolerability study. We looked at five dose cohorts, 18 patients, and from that we saw very good safety. We did not hit a maximum tolerated dose, so our high dose of 20 mgs, we'll be moving forward with that in the phase I B/II expansion study. That study has also started.
little bit of a different design from the standpoint of, in the phase IA, we looked at all comers pretty much from a safety perspective. Here we're looking at a narrower range of tumor types where we're actually requesting biopsies, selecting those individuals that have high levels of B7-H4 expression. We've developed a CLIA-validated test, where we can now look at where we've also defined some H-scores that are cutoffs to enroll those patients that we think will be most responsive. This, Alec, gets back to your question kind of on NC318. What did you learn? You know, we're always questioning ourselves, but I think we're a much stronger organization in the tools that we're applying to select those patients that we think will both be most responsive to these novel immunomedicines that we're pursuing.
Great. That makes sense. Is the assay, one that's off the shelf, something standardized, or did you have to also develop this from the ground up yourself?
It's off the shelf in NextCure's lab. It's a test we developed. We develop all the tests internally. Since we have our own development and GMP manufacturing labs, we can develop all the critical reagents internally. That becomes really important if you're trying to maintain consistency from assay to assay. Once we've got the reagents, we actually develop the assays in-house to make sure that they have the specificity and sensitivity we need to utilize in a clinical setting. We conduct the tests internally. We do the analytics internally. Then we try to feed back that information in real time to the clinical team. Happy to announce, in August this year, we actually launched our own GLP lab.
Most of these clinical samples usually go to a CRO for testing. We wait, you know, patiently for the data to come in. At this point, we've tried to kinda cut out that, you know, middle step. Now the clinical samples are sent directly to NextCure. We have a lab already established with a GLP criteria. We can now do the testing. In real time, as I mentioned, share that information with the clinical team so that they can understand what's going on mechanistically with the drug and how some of these PD markers may play into making any adjustments in the trial moving forward.
Oh, that's great. That's great. On NC525, I believe you've got a trial in progress poster coming up at ASH. You know, any unique considerations around how the study was designed that you flag? I know, AML has been a difficult disease to get a foothold in terms of drug development.
Yes, definitely a difficult disease. We're actually really excited about NC525. This is our segue into the heme-onc space and this is an antibody that targets LAIR1. It works completely and mechanistically different than our NC410 LAIR2 fusion. As you mentioned, we actually at the ASH conference next week, I think it's Monday, we'll be presenting a poster regarding a clinical trial in progress. The trial's been designed to look at AML patients. We'll also look at some other heme-onc patients as part of that study too. The phase I will be a traditional dose escalation, safety, and tolerability study, but we should be able to generate enough data to have some sort of a clinical update by year-end next year.
What's interesting about this antibody, unlike, you know, many of the other, you know, drugs that are being developed, is it specifically kills the leukemic stem cells in the glass. More importantly, it preserves the hematopoietic stem and progenitor cells. From a safety perspective, we're hoping and anticipating that this will be a very effective or potentially effective, you know, drug treatment for AML patients. The mechanism of action is pretty exquisite, you know, from the standpoint of various signaling pathways and how those signaling pathways are impacted with respect to the leukemic stem cells versus perhaps not being impacted in looking at the normal hematopoietic stem cells. We're really excited about getting to dose our first patient. Our team is going to the ASH conference next week, so looking forward to updating on everyone next year on this program.
Great. Yeah, we'll be there as well, so we'll definitely look out for the, for the poster. I just have one question. This is more of a philosophical question, I guess, for you, Michael. It, it is one that we've received. It, it doesn't just apply to you guys, but the--scape as a whole. There have been, you know, a lot of good targets identified, TIGIT, you know, many others, but very few have, you know, I guess, played out in the clinic, as monotherapy or in combination with CPI. I guess my question is, you know, how are you guys leveraging the wealth of targets that have come out of FIND-IO™?
How do you tailor the best drug, whether it's a small molecule, an antibody, you know, an ADC, you know, with your new LegoChem Biosciences partnership, to sort of reap the most benefit out of those targets?
Yeah, excellent question. You know, we look at things where we have to get three things right, Alec. We gotta get the target right, we have to develop the right candidate, and then we have to go into the right patient population, and all three of those things have to align. First and foremost is, as you mentioned, the target. We go through an extensive screening process to evaluate and validate our targets. Once we identify a target, we go through what we call the three Rs, reproducibility, robustness, and then relevance as it relates to cancer or perhaps another disease. We did spend a lot of time looking at expression profiling, both on the genomic and proteomic level.
You know, even if it's over expressed on many tumor types genomically, looking at different databases, we then actually look at tissue samples, tumor microarrays, to look at the expression profiling. As one would imagine, we do a lot of animal modeling, both in monotherapy in a combination setting. Your broader question is, you know, there are a lot of candidates out there and, you know, why aren't we seeing more effectiveness in the checkpoint space? First of all, immunology is challenging, but I think we're learning a lot. There's a lot of great science being done. I think combination therapies or modified antibodies or even certain small molecules or RNA elements, you know, will play important roles moving forward. We're doing a lot of thinking beyond combinations, but also looking at the sequencing of events.
You know, it's not like, you know, the immune system, everything, you know, turns on at the same time. There's a certain sequencing events that we need to kinda consider. We also go with the science. In the case of the LegoChem Biosciences deal, we're really excited to work with the LegoChem Biosciences team. They're outstanding at what they do with respect to developing various payloads and linkers to modify antibodies. Our first of three targets will be anti-B7-H4 as a next-generation molecule. This will be either a next-generation molecule or potentially used in combination with NC762 itself. One could imagine coming in very hard with a molecule that has a chemical payload and then looking at a naked antibody in the context of maintenance therapy.
Our scientists are investigating a lot of these different types of approaches to maximize the effectiveness of the targets. Next, by looking at a lot of targets versus a company that may be just looking at one, you learn a lot. Each of these targets has its own distinct biology, impacts different types of immune cells, T-cells, NK cells, like in the case of B7-H4, macrophages, in the case of Siglec-15. By understanding the repertoire of immune cells and how they're behaving in the tumor microenvironment gives us great insight into how to drug a specific cancer.
I think the combination of having the platform, the three clinical candidates, the multiple tumor types we're focused on, and looking at combinations and ADC approaches, I think really differentiates NextCure from the standpoint of being driven by the science, but also aligning the science with distinct, meaningful product development approaches.
Great. Great. Maybe in the last 30 seconds or so that we have, maybe we can just wrap everything up in terms of, you know, upcoming catalysts to look out for. You know, what would you sort of flag as being maybe the most meaningful or ones that you're most excited from the pipeline?
Well, we love all three of our kids, or maybe four, I guess. you know, we're really excited about, you know, the three clinical programs moving forward, the updates that we'll provide next year. We've got a fully integrated infrastructure that can continue to feed and grow the pipeline, continue to build value. We've got a strong balance sheet of $169 million as of the end of last quarter with a long runway into mid-2025. That really kinda sets the stage for now executing on our plan. I think you brought up a really good point earlier with respect to, you know, lessons learned from NC318, our biomarker capabilities, and our ability to kinda execute and advance our programs.
I'm excited about the upcoming holidays, but I'm also really excited about our platform and our pipeline and our people and really, you know, seeing how hopefully the impact our drugs will have on patients next year.
Great. Great. We'll definitely looking forward to those updates. I think for now, that's all the time we have. I wanted to thank you, Michael, for taking the time to participate in the conference and for the great discussion.
Great. Well, thank you, Alec. We greatly appreciate it. We also, appreciate the opportunity from Bank of America to participate in the conference. Thanks again for your ongoing support.