Okay, we'll continue with the next session. For those of us joining us online, I'm Paul Choi with the Goldman Sachs Biotech Team. Our next session is with NGM. We have Dave, CEO David Woodhouse, and CFO Siobhan Nolan Mangini in the audience as well here. Maybe what we'll do, David, to start is just at a high level, starting with strategy, can you maybe characterize NGM's model of in-house drug discovery and, you know, how you and the management team think about maximizing R&D productivity? Sure, thanks for the invitation to the conference, Paul. Yeah, at its core, NGM is a biologics discovery platform. We've been at this for 15 years now. We've generated 11 INDs over time. Really, all of the programs that you see in our pipeline are certainly homegrown. The way we think about it is, really, we have teams of scientists looking in different areas across interesting biological pathways that we think could be interesting to drug. Then we pair that with our protein engineering expertise. It's created this portfolio, and really, our strategy as a company is to use both business development and take something forward on our own. The other core aspect of NGM is really to use the data to tell us, you know, what deserves to be taken forward, and what maybe is telling us there's signals in another area to pivot into for it. We do think about it as a portfolio. It's renewable in that there are, you know, new molecules coming out of the engine all the time. We've, you know, just, our strategy is really to use the data to drive, tell us where to take molecules into development. Okay, great. The initial focus when you went public was on NASH. Now you are primarily focusing on oncology. Mm-hmm. Maybe from your perspective, and as you think about the assets you have, in-house, you know, for the assets you have, what is sort of the white space in oncology, and, you know, how do your pipeline assets potentially fit in there? Yeah, the reason our development resources are focused on oncology now is because we see it as a very fitting area for a smaller team to go into and generate data relatively quickly. The white space we saw in oncology was specifically around kind of a new angle on IO, immunotherapy, which is... We had observed some great advances with T-cell checkpoint inhibitors. When you look at why many patients aren't responding to T-cell checkpoint inhibitors or becoming resistant to them, the myeloid cells that are present in the tumor microenvironment really stick out as another checkpoint area to go after. The strategy for 3 of our programs is really targets that are associated with those cells in the myeloid compartment, that look like they may be driving that resistance mechanism that is associated with myeloid cells. What I think some people forget about in a tumor, is a tumor is actually composed of a large component of immune cells. Many of those are actually myeloid cells. The cells are there, they're just doing the wrong thing. These, the opportunity we see this program, with these 3 programs in IO for us, it's actually just flip the switch and reprogram those cells to invite immune attack by T cells and natural killer cells, rather than suppress them. Okay. Maybe going into some of the assets, specifically, David, starting with NGM707. It's a very interesting approach, where you're targeting ILT2 and ILT4. People may be somewhat familiar with the category because Merck did some work in the area as well earlier. Can you maybe start with, you know, how NGM707 differs from the Merck asset, and just kind of the general premise of targeting these 2 particular areas as checkpoint targets? Sure. Yeah, we, IO targets, rather. Yeah, right. Yeah, we got interested in ILT4 and ILT2. They rise to the top in terms of targets on these cells that seem to be associated with this resistance mechanism I was referring to. We're certainly, our team created monospecific antibodies against both targets, but the innovation we brought to the table is, we actually designed an antibody that can block both at about the same affinity. That's almost like a combination drug already. We knew biologically what makes sense ultimately with these targets, is to combine them with a T-cell checkpoint inhibitor, so you're getting over both checkpoints or helping the patient get over both checkpoints. We thought, as long as we can do this safely and hit both targets, that's actually a big advantage. One of the reasons why is that, when you look at evolutionarily, where these receptors point to in sort of monkeys and rodents, they're a relatively new invention, so to speak, in the genome of humans. In that, in monkeys, there's 1 version that was duplicated, and ultimately in humans, that's created ILT2 and ILT4. The reason I raise that is because part of the thesis here is these are redundant receptors. They're structured very similarly. Their expression patterns look very similar. There are some distinct advantages to ILT2 also, in terms of where it's expressed in various cell types, including some effector cells, like B cells and natural killer cells. So. You know, what we're pleased to see is it appears that we can safely block both receptors, and therefore it adds a whole nother dimension than just inhibiting ILT4. Okay. From a safety perspective, I guess, you know, one of the classic issues with whether it's targeting PD-1 or CTLA-4 is various immune reactions. Mm-hmm. How does maybe your early data and sort of proof of concept and preclinical work suggest the practicality from a safety perspective, maybe of NGM707 targeting ILT2 and ILT4? Yeah, we looked at that very closely preclinically. You wanna see cytokine expression, and you wanna see the right switch. That's really the way to measure this phenotype switch I was referring to, of cells going from sort of a suppressive state to an inflammatory state through cytokine release. When you're in a patient, of course, you don't wanna trigger those sort of immune-related side effects. You know, our strategy, and, of course, in dialogue with the FDA, was actually to start pretty low in our monotherapy dose escalation. What we shared at ESMO IO last December, was our interim look at our phase I-A that showed that from a safety perspective, we don't seem to be experiencing those types of immune-related side effects in any sort of concerning way. Okay, great. You mentioned the data you presented late last year, and you are doing an ongoing study of it, both as monotherapy and as in combination with Pembro. How do you think about the cadence of data for your NGM707 program, and how you're gonna present that over time to investors? Obviously, you're still working through dose determination and things like that, but maybe just, you know, walk us through the sequence or how you're thinking about that potentially. Sure. Why don't I just start by describing kind of our development strategy, and then I can explain how we think about disclosure around that? I referenced the monotherapy dose escalation. This is the phase I-A. We have effectively completed that. We certainly completed enrollment. We have also done the combination dose escalation, the phase I-B portion, with Pembrolizumab or KEYTRUDA. We've announced that we've started our expansion cohorts, which is technically considered a phase II. The data we've shared so far was the interim on the phase I-A that I mentioned at ESMO IO in December. The strategy we have for disclosure, for going forward with the program is, we heard a lot of frustration generally from the external world about dribbling out data over time that makes it difficult to really assess, you know, how are you going to make a decision about what to do with this program? Our approach with 707 is actually to accrue a fair amount of data before we actually disclose it. What makes it difficult, therefore, is to predict which medical meeting you will have that data, because patients obviously have to be enrolled, and you have to follow them. Generally, what we've said is that could be later this year, it could be sometime next year. We aren't giving a specific meeting, for instance, to watch for. We do plan for it to be kind of a look across all of that, group, the phase I-A/1-B, and part of the phase II as well. Sure. maybe focusing on the phase I-B for a little bit, you know, obviously, one of the dreams in immuno-oncology, with particularly with combination approaches, is to show 1 plus 1 can equal 3 or more, or something like that, something that's truly synergistic versus just additive. Mm-hmm. I guess, you know, how do you think about the potential there for something that could be more synergistic versus additive, with regard to Pembro and your NGM707 development? Mm-hmm. Yeah, it depends a lot on the tumor type and the setting. Mm-hmm. Each patient here is able to gain a lot of information because, of course, what we're looking for are opportunities to enrich patients that are responding, follow biomarkers and things like that. I'll give you an example, which is, I think it's fairly well known that CRC patients don't respond to Pembro. MSS CRC patients don't respond to Pembro. In terms of synergy, or it's not really synergy, but it would be pretty terrific to show when you use a combination approach like this, you're able to actually generate response in patients that normally wouldn't respond. You would go to the other end of the spectrum in what are considered hotter tumor types. That becomes a little more difficult because there are certain rates of Pembro response, for instance, that you'd need to be mindful of that when you're seeing responses. Taking it even a step further in terms of how long will we have to go until we know whether we have a advantage hitting both ILT2 and ILT4 versus monospecific ILT4, I think that'll take a while. We are watching with interest, the ILT2 monospecific antibody that Sanofi and Beyond Therapeutics are developing. Mainly because, at a minimum, if they're seeing something, Merck, with their ILT4, appears to be seeing something, that we should at least be those 2 things together. The way I think about it generally is, it's hard to tell why a patient is resistant to therapy. What we're providing with a dual approach here is having to take the guessing game out of it, which is, we should be able to either capture more patients or provide those patients that respond a deeper response. Just because we're covering more ground with our antibody. Great. You know, you talked a little bit about like an opportunity, like in CRC, where traditional IO approaches don't generate meaningful responses. Are there other, you know, as you've screened sort of the landscape solid tumor types that you view as most opportune for development? Yeah, we're starting to see some patterns, both within our own data, but also when you look at some of the mono-specific IL-4s being developed. Certain gastric tumors seem to we're seeing responses in the landscape. Ovarian is another area. Another interesting, because gastric you would sort of predict based on screens of what tumor types tend to have overexpression of ILT2, ILT4. Ovarian, you might not. You know, we're often reminded that you can't be too smart about. You can't think you're too smart in working with some of these biomarkers. I think PDL1 has been a great example of that, and that there are some patients that appear to have no PDL1 expression that respond to anti-PD-1 therapy, for instance. It's obviously better, you see more responses with higher PDL1 expression, but you do need to take a fairly broad lens, keep an open mind when going into these early studies about where and how you're gonna see signal. Okay, great. Maybe turning to other drugs in the portfolio and NGM120. you know, that's been a drug that's been in the clinic for a little while. You and you've had some success and interesting results with prostate cancer. Can you maybe, you know, describe that for us and, you know, kind of where you would think about developing it in prostate specifically? Mm-hmm. Yeah, the observation that we've made is that in our monotherapy dose escalation with NGM120, we had a gentleman who had a very strong response from both a PSA biomarker drop and a tumor shrinkage biomarker drop. We're exploring it in a small cohort to see if we can reproduce that. That'll be important to decide whether there's something there to work with. This is admittedly fairly high risk, and we hope high return science, in that the mechanism isn't as straightforward as I was just describing to you for-. Mm-hmm NGM707. This is an antibody that binds a fairly small set of receptors. Well, the receptors are expressed in a fairly small set of neurons in the brainstem and blocks this hormone called GDF15. We know that patients who have cancer patients with expressing high levels of GDF15 tend to have a worse prognosis. It's sort of a general correlation that this could be useful to block this pathway. The biology behind it is fairly complex, in that GDF15 has metabolic aspects to its activity and immune regulation. We and a couple of other companies are exploring whether this could have application in cancer. It could also have other applications in some other disease types we're following. In this resource environment, we're being very careful with this program, given kind of the risk profile, about whether we want to, kind of invest further in oncology with this program or perhaps take it into more orphan indication, that may make a little more direct sense. To your point on thinking about this strategically and carefully allocating resources, maybe, but just within the prostate cancer category, would this be patients who had failed prior Zytiga and Xtandi and other options, just a very late line population, or people who had maybe are potentially earlier in their lines of treatment? Yeah, it's a great question. It's one of these issues we face in oncology, especially when you've got an immune component to it, in that patients' immune systems tend to be stronger and potentially more valuable to attack a tumor when they're earlier in line. It gets complicated just from a strategic point of view about how you position your agent there and how competitively is it positioned. We're more likely to go later in line to see if we see that effect rather than earlier. I think over time, it would be interesting if we do see something to actually step it earlier. There are instances of patients who kind of that intersection between those hormonal therapies and sort of the next therapy, which tends to be a chemo agent. It's actually a pretty opportune area to test because a lot of those men don't necessarily want to go on a chemo right away. They want to see if they'll either just fight the disease themselves or, at least entertain something that has a better side effect profile than chemo. Pancreatic cancer remains one of the more intractable solid tumors, this is another area you're exploring with 120. You had some results there that were pretty interesting. Can you maybe explain that to us? You know, how does this underpin the rationale for your phase II PINNACLE study? Yeah, we took NGM120 into pancreatic cancer because it's a tumor type that's highly associated with development of cachexia, cancer cachexia. I think the images of Steve Jobs or Patrick Swayze are etched in a lot of our minds and just that wasting syndrome that occurs and often kills many pancreatic cancer patients and other cancer tumor types. It's a tough cancer type which allowed us to look for both potential anti-cachectic effects, but also direct anti-tumor effects. In our earlier studies, we've seen some encouraging signs of survival benefit compared to the standard of care, which these patients are also on, which is gemcitabine and Abraxane. Which, by the way, in and of itself, chemotherapy elevates GDF-15 and causes, potentially, we think could worsen this cachexia by promoting that. There are a couple of ways to win in this population about whether you can just keep the patients healthier so they can receive more chemotherapy, or can you have a direct effect on the tumor itself? It is a tough tumor type. It's a tough cancer type to treat. Those early data are what inspired us to run the PINNACLE study, which is a study designed to have an arm that's just standard of care, Gemabraxane, another arm, gemabraxane plus NGM120, and see if we see a difference with NGM120 treatment. We also have quite a large database of historical response rate survival with just standard of care chemotherapy. Great. What's sort of the status of the PINNACLE that you kicked? Yeah Kicked off a little while ago? PINNACLE was fully enrolled, and so we're at the stage where we're tracking patients. We haven't guided on timing for results yet because we have to track those patients, but we are fully enrolled. Okay, great. You also mentioned your other area of development, which is for cachexia. You know, I guess there are a couple of ways to think about. Yeah of developing NGM120 here, which is, 1, is prophylactic, and then 1 is as a sort of an adjunctive treatment for patients who are undergoing, you know, treatment for other areas here. Can you maybe separate those 2 out for us and just how you think about its potential role there? Yeah, The cachexia angle could be really interesting. Unfortunately, the regulatory path for that isn't certainly not as well-defined as an anticancer agent itself. We've watched with great interest in that Pfizer has an anti-GDF15 antibody that they're developing in fairly late-stage cachexia. We think that's really interesting to follow them. And they will... We're not planning to necessarily dive into that partially because of that regulatory concern. It's interesting. It's not to say that the regulators aren't really interested in trying to encourage development in this space. I think there's a willingness to consider different endpoints. There's just not a proven path. Yeah to follow yet. It's certainly ambiguous. Okay. You also have other assets in the clinic, namely NGM438. Mm-hmm ... which is ongoing there. Can you maybe remind us, you know, how it works and just what your development strategy is there? I have a couple follow-up questions. Okay, sure. NGM438 is an antibody we developed to target a receptor called LAIR1. It's a similar story to what I described to you around ILT2 and ILT4, and it's a receptor associated with resistance or this kind of idea of a myeloid checkpoint. The difference with this receptor is its ligand is collagen. This and our program called NGM831, which targets a receptor called ILT3, are both around this biology we term a stromal checkpoint. Certain tumors have extra or more extracellular matrix associated with them that appears to drive more of a resistance mechanism. The theory here is that extracellular matrix actually signals to the immune system to switch to that resistance rather than inflammatory response. LAIR1, we think, is a key receptor for doing that, and that's why we're trying to block it and help patients overcome this resistance mechanism. This program is in the same sequence as I described for NGM707, so monotherapy dose escalation. We've advanced it to combination dose escalation with pembro again. We'll use the same data disclosure strategy I described, which is accrue more rather than less data points. I guess, given that you have multiple assets, you know, dedicated to IO, I guess, you know, for, in your mind and the management team's mind, you know, what do you need to see, I guess, to think about these assets as going forward, in terms of and being sort of viable assets that you wanna continue to invest in from a future R&D spend perspective, given that, you know, oncology obviously is a tough and somewhat capital-intensive space? What's sort of the litmus test that you and the management team apply here? Yeah, it's a great question. These are relatively expensive trials to run, we do plan to keep these programs on a relatively short leash, just in terms of... I think it's important to get to a proof of concept point of some kind, but let the data tell you whether to move it forward or not. There's definitely a reason we're bringing multiple programs together. We'd certainly love if they all work, but you really just need one of them to work and then really shift resources to pushing that 1 forward as quickly as possible. With NGM438, an example of how we're trying to spread this need a little bit, as I mentioned, the strategy or the theory of the stromal checkpoint, we're actually planning to combine in a, what we're calling the triplet strategy, NGM438, NGM831, and pembro in a dose escalation phase 1-B. That will allow us to test, are we seeing an effect that you wouldn't expect in these late-line patients? If we don't, then we've actually answered the question for both programs rather than running them independently. Mm-hmm ... and spending more money. You know, I mean, generally, it depends on the tumor type in terms of what kind of effect rate you're gonna kind of call the question on in these expansion cohorts, which is, generally kind of 20% plus effect rate. With the exception that in the tumor types that don't respond at all to T-cell checkpoint therapy, that's probably a little bit of a lower bar. Mm-hmm. There. We, you know, we're trying to get to these questions as quickly as possible in the interest of resource management, and follow signals where we see them. Maybe turning to other parts of the portfolio. Mm-hmm. you know, as I said earlier, at the beginning of our discussion, you were originally a NASH company and with Aldafermin, despite it not working in F2 and F3 patients, you recently had a clinical win in F4. Congratulations on that. Thank you. You know, first, you know, can you review the data, how the, you know, what kind of patient population did you test Aldafermin in here in the F4 subgroup? I had a couple follow-up questions there. Sure, yeah. This was a trial called ALPINE 4. It was a phase II trial in F4 patients, so these early cirrhotic NASH patients. The strategy we used here, we had 2 active doses, and a placebo arm, and the primary endpoint was a little unique here, and that was a biomarker called ELF, which is a 3-component biomarker. It's actually approved on diagnostic panels for the diagnosis of NASH. To be clear, it's not any FDA-approved surrogate approval endpoint, but it is handy because it's a continuous variable, as opposed to, let's say, fibrosis, which is F4, F3, F2, F1. We measured that. What we hit on the primary of ELF, was a significant reduction, statistically significant reduction. The reason that's important is because, as opposed to F2 and F3 NASH regulatory path, where you have available these surrogate endpoints of either NASH resolution or fibrosis reversal, in F4 NASH, the FDA has not blessed those surrogate endpoints. They want an outcomes trial. The reason we picked ELF as our primary endpoint is, ELF is a well-correlated biomarker based on some natural history studies with outcomes. We thought it was a useful endpoint to track in a phase II, to predict should you see something if you were to run a phase III outcome study? The answer appears to be yes, dose response. We also saw supportive data from the biopsy portion of the trial that showed fibrosis. 20% of the patients saw a reversal of fibrosis as well, and by biopsy. It's always handy when the biomarker trends with the actual other endpoints you're looking at, and that was the case. This is the 1st positive study in F4, I think you meant non-cirrhotic population, or... They're cirrhotic. They're cirrhotic. Yeah, yeah. Excuse me. Sorry. Yeah. cirrhotic population. sorry, you mentioned earlier on the regulatory point that here, the FDA does want harder clinical endpoints- Yeah. versus surrogate endpoints. While the study wasn't intended to be an outcomes, study, you spoke a little bit about fibrosis. Can you maybe speak to some of the other things or other, clinical endpoints that you were able to observe, even though it wasn't necessarily a longer-term study? I should have mentioned, it was a 48-week treatment period, so it was a year-long treatment. Yeah, I think the interesting part of the study actually was we saw relatively few outcomes, quote, unquote, "outcomes in patients" in the placebo or treatment arms. Suggesting that to run a phase III outcome study in the F4 NASH population is a pretty big lift, actually, which is why we've, even before we ran out the study, we've indicated this is a partner we're a program we're likely to partner for developing it in. Mm-hmm. F4 NASH. We think the setup is actually pretty good there for the opportunity to show an effect in F4 NASH. Of course, we have to consider also the competitive landscape, so we'll be watching with interest as some of the FGF21 analogs report out data in F4. The unique opportunity we have with Aldafermin is, it's an FGF19 analog. It's the only FGF19 analog in development, the biology is really potent around bile acid control with this mechanism. So we're interested in also having conversations with partners, but even possibly considering taking Aldafermin into some of these cholestatic disease settings, which we actually already have data in. We also, in addition to ALPINE 4, at the same time, shared some data around bile acid malabsorption. Those seem to be really interesting, well-tied to the mechanism, opportunities that the agent has as well. That's great. Maybe the last 1 on this subject is, and you kind of referenced it, indirectly, which is to think about, you know, we might be on the verge of the 1st approved NASH therapy in the not-too-distant future. I guess, you know, the questions obviously remain on what the label will look like and what sort of populations, you know, these drugs might be used in. How does that, I guess, in your mind, you know, as you think about partnering out Aldafermin, you know, affect the potential opportunity there? Yeah, I think those will be important things to follow. We obviously had an Intercept AdCom recently that didn't go so well. But it's, you know, Aldafermin is a once-daily injectable that in some populations requires a concomitant statin use because of the LDL increase that mechanistically we would expect. So we have to watch that carefully, especially in these sort of earlier asymptomatic patient populations, which is exactly why I was referencing some of these other slight symptomatic, more orphan indications, but tied really well to the biology. You know, when you rewind the clock at NGM, when we 1st got into NASH, we didn't know necessarily whether it was the FGFR1C pathway that FGF21 and FGF19 hit, or is it a combination of FGFR1C and FGFR4 that is best suited? I think it's probably the FGFR1C pathway, actually, that's driving a lot of the effect we're seeing in NASH. Separate from that, the beta thyroid angle has, you know, purely a metabolic effect. That seems to be a powerful way to treat NASH. Okay. We have a few minutes left here, so maybe turning to some bigger picture strategy questions. As you think about business development and future capital, you know, and sources of capital, you know, how do you prioritize that? You know, how are you thinking maybe about specifically about allocation of capital in this current environment? Yeah, we certainly think it's important to spend a lot of time on that as a management team, particularly in this environment. The history of NGM, as we've used about of the capital we've raised, about half of it has come from business development and half from capital markets. When we're talking about a portfolio that is this broad, I think that's an important metric to continue to strive towards. We have quite a few assets to work with on the business development front, the trick is always is how much do you do on your own and when do you need a partner? That's both resource and capability-driven. In the instance of these metabolic indications, in the instance of ophthalmology, for instance, that's a pretty obvious place for us to look for partners who maybe have an expertise in those areas to take forward. In oncology, that also could be the case in that, particularly for these pan-solid tumor applications, that's a pretty big development. You can look at what Merck has done with their anti-IL-4. It's quite broad, I think a dozen tumor types, all sorts of different combinations. That's another instance in which we might partner earlier rather than later. You know, we are interested in producing that proof of concept, clinical data that matters so much to driving value. Then also being really disciplined about data, telling us to make decisions. I think we've done a reasonably good job of that historically. When you look back to ALPINE 2/3, it hit NASH resolution. We could have taken that forward to a phase III. Guess what? We kept a really high bar for that data set. We wanted to see fibrosis reversal. We didn't see a dose dependent, 1 milligram arm surprised us a little bit. The competitive landscape has changed, and so I think that was a good decision in retrospect. Look, we were still surprised by NGM621 results in ophthalmology, but the data told us not to move forward there. Great. I want to close it out, maybe just with sort of thinking about what's next and your pace of INDs and cadence of INDs. You've put, you know, several oncology drugs into the clinic over the last couple of years, and maybe could, you could speak to, in our closing minute or 2 here, just how we should think about new INDs and new assets coming being disclosed and going into the clinic. Sure. Yeah, we did do a restructuring of the company earlier this year. One of the things we thought was important to maintain, though, is enough of the critical mass in the discovery area to be able to produce new INDs over time. Our pace has been about 1 new IND every 18 months or so. We continue to strive for that. We did push all 3 of these IO candidates in pretty quick succession into the clinic. You know, science is science. We don't have an arbitrary time. We like the molecule to declare itself and almost force us to nominate it and take it forward. In this environment, though, we have to decide, is that something we can afford to actually put in the clinic ourselves, or is it something we might partner preclinically, for instance? Our last nomination, NGM936, for instance, we, that's exactly the strategy we've taken. Okay, great. We're all out of time here, so although I'm good on that note, my thanks to David and NGM for joining us today. Thank you very much. Thank you, Paul.