All right. Good morning, everybody. Thanks so much for joining us here at Guggenheim's Healthcare Innovation Conference. I'm Seamus Fernandez, one of the Senior Biotech Analysts here at Guggenheim. Really pleased to be joined by BioAge. Immediately to my left is Kristen Fortney, Co-Founder and CEO. Kristen, maybe just to sort of kick us off, let's start off with a high-level overview of BioAge's focus and how the platform and the pipeline really support BioAge's mission in particular.
Yeah, for sure. And thanks, Seamus, for having me here today. We're pleased to be here. Looking forward to the conference. Briefly, BioAge is focused on, we have a platform based on human data, and specifically longitudinal human aging data, to find pathways and targets that are important for metabolic aging, healthy lifespans. It was that data that led us to NLRP3 as well as APJ, where we have programs running, as well as preclinical collaborations and preclinical programs that we'll speak to, I think, later. Broadly, right now, our lead product is BGE-102. This is a potential best-in-class brain penetrant NLRP3 inhibitor currently in two phase II clinical trials, with data coming later this year, as well as in the second half of next year. This is a target with many different potential applications, from cardiovascular to ocular to neuro.
We're really looking forward to those imminent readouts. I'm sure we'll speak about all of that in greater depth.
Yeah.
We're also really excited to be back in the clinic again soon with APJ, so we're on track to file IND by end of this year, and that's when we'll give our sort of clinical timing as well for this really exciting target that's relevant to obesity and muscle.
Great. Just in terms of picking the targets, the longevity approach is potentially useful in picking targets. Can you talk a little bit about the approach itself and the platform?
Yeah, for sure. What is unique about our data, and this is partially inspired by data sets like UK Biobank or deCODE genetics that Amgen bought, have been so useful, but they are not necessarily the best data sets for understanding aging, because the length of the follow-up, like they often have longitudinal samples from people, but maybe one or two over 10 or 20 years, right? What we wanted to do is we wanted to understand disease before it starts, right? You can look, there is a lot of diseases that happen to you when you are 80 that do not happen when you are 20. So something is very different about your body when you are 80 versus when you are 20. We wanted to create a data set that was like UK Biobank, where the key difference was the length of the follow-up.
We have thousands of samples from these great population data sets where we have 50 years of longitudinal samples, right? So that first sample is collected when someone is middle-aged and healthy. You have them sequentially profiled through time until their death, and you can go into that sample, measure all the proteins, all the metabolites using today's technologies, and correlate that to future outcomes. Like, what is different about those individuals who went on to live healthier and longer than the rest of us? What is different about those people who had improved physical function with aging or improved cognitive abilities, right? So those are the kinds of questions we ask of the data.
Got it. Just in terms of partnerships that are ongoing, centered on the platform, just what are the goals of each partnership and any milestones that have been reached?
Yeah. We have two pharma collaborations on our platform, on our human platform. The collaboration with Lilly is around a couple of targets that are novel that we think are exciting from our own data, and they are helping us build molecules. The collaboration with Novartis is a bigger one. To be clear, those Lilly programs would be ones that we would bring inside. They would be part of our clinical pipeline eventually. In contrast with Novartis, that is really like a big discovery collaboration. Novartis, like us, is really keen on human data as sort of de-risking for drug discovery, and on aging too. They have a whole department of aging research under Fiona Marshall. They really wanted to look with us about the intersection of what is important for human aging and what is important about the response to exercise.
Because a lot of these, your ability to maintain muscle mass, things like that, declines as you get older, and that is related to aging biology, but also exercise biology. So it is really a big integrative exercise to find novel targets. They are explicitly interested in things where people have not built programs before, and we are going to advance some of those. Some of those will be targets that BioAge works on, some of them will be targets that Novartis works on, and that was a deal that came with upfront milestones, FTEs. It is a great way to fund the expansion of our platform internally as well. Yeah.
Great. Let us talk about NLRP3. Let us start first with what is unique about BGE-102.
Yeah. This is a target that there are a few other programs out there. We initially got excited about it because of our human data, and specifically, in our human data sets, having elevated NLRP3 predicted shorter lifespan, and specifically accelerated cognitive decline. So from the outset, we really wanted to build something that was brain penetrant. That was part of our design goal. We also wanted to build something that was different from the original molecules, like the MCC950 with Pfizer, et cetera. We set out to eventually discovered a novel binding site, so we have the only novel binding site to NLRP3, distinct from the same binding pockets that everybody else is working on. We went on to characterize that binding site.
We published the crystal structure with Matthias Geyer, who is the sort of expert on NLRP3 structural biology, and there is a few unique features of this binding site that could translate into potential advantages. The most important one is that our binding site is available when the NLRP3 is both active and inactive.
In contrast, the other binding site that everybody else binds into is only available in the inactive state, right? So that could translate into faster onset of efficacy as well as deeper efficacy. We have seen so far in our phase I data set that we released back in April, best-in-class reductions in IL-1β and the other inflammatory biomarkers that you look at to look at target induction here.
Great. In terms of what has been shown so far, maybe we can kind of jump straight to the magnitude of effect on CRP, IL-6, IL-1β, as well as the safety and tolerability that you have seen so far.
Yeah, for sure. So we released a data set back in April which included healthy volunteer SAD/MAD, but we also looked in a couple of obese cohorts as well, so people with obesity and elevated inflammation at baseline. That is because with this class, you can see such a rapid reduction of inflammatory biomarkers, like you can see it in a week. What we demonstrated is a few things. So, as I mentioned, best-in-class IL-1β reduction, so up to 98% IL-1β reduction depending on the dose, which is, to my knowledge, the highest that has been shown. Best-in-class CRP reductions as well. This is an inflammatory biomarker in a number of diseases, 86%. Similarly for the other biomarkers that people look at here, fibrinogen, et cetera.
Potential best-in-class profile, and all very well tolerated to date, really not different from placebo in the phase I data so far.
Great. QUELL-CV, so we are on the cusp of data. Can you maybe just describe the study, how you are thinking about dose response, and the effect size?
Yeah. QUELL-CV is originally inspired by the Ventyx study, where they looked at an obese inflamed cohort for three months and saw some really profound biomarker reductions, and was also, the original thinking was to inform cardiovascular disease. That is all shifted in the wake of ZEUS, and we can speak to that. But QUELL-CV is still a really important study for us. As I mentioned, these are people who at baseline are obese, have high inflammation, and so these individuals are at a risk of a whole bunch of different diseases, whether it is MASH or diabetes or cardiovascular. They are taking our drug at three different dose levels, 30 mg, 60 mg, 90 mg, once a day for a three-month period. We are looking at a very rich set of metabolic and inflammatory biomarkers, including the canonical NLRP3 pathway ones, but more broad as well.
We are also looking at MRI to look at liver inflammation, DEXA. We are going to learn a ton from this study in terms of the potential future application areas of the drug, in terms of the long-term safety, and also in terms of that dose that we will carry forward, right? Because right now it is an open question. Part of the reason we are doing dose ranging here is that we are definitely maxing everything out at 90 mg once a day. That should give us the complete IL-1β inhibition. But 60 mg might be just as good. So we will know the answer coming out of the study.
Got it. Okay, great. Just in terms of some of the dynamics in the market today, there is a lot of data to suggest the relevance of IL-1β. Unfortunately, IL-6 has kind of hit a pretty hard stumble with the ZEUS results. Maybe you can just help us understand the interpretation of ZEUS, how you have looked at that data set, and then what it teaches us, but also what it does not teach us.
Yeah, for sure. No, ZEUS was, of course, was a big setback for the field, a big surprise back in July, and we just heard the deeper look at that from Paul Ridker at AHA just on Saturday and on Sunday. Overall, again, this is IL-6, so this is very downstream relative to NLRP3.
Yep.
It failed to show an effect in a cardiovascular outcome study. The hazard ratio was close to one. This is in the context too, the reason why they looked at this in the first place was because they saw a significant difference with IL-1β, right? So IL-1β is a different target, not affected by IL-6, but that is directly downstream of NLRP3, and we can speak to that in a minute. But in terms of IL-6 itself, coming out of that study, the two potential possibilities are either it is the wrong population, so the famous CANTOS study where they showed that IL-1β inhibition had a really nice effect on MACE outcomes, up to 25% as a function of CRP. That was in a healthier population relative to ZEUS. So a number of people in the ZEUS study had quite low GFRs.
They may have had events that were unrelated to inflammation, right? But the other possibility, of course, is that it was the wrong target. Like IL-6 is very downstream. It produces CRP, it is certainly upstream of CRP, but maybe not of much else. I think in the wake of ZEUS, Paul Ridker spoke to this, and Novo is very explicit about this as well, they are looking to upstream targets like NLRP3, where you are definitely going to get that IL-1β suppression, which previously has worked, and where it is also more related to the data you see with colchicine, which is also an upstream drug that works.
Yeah. Clearly, the industry hasn't backed off of NLRP3 as a key target, not just for cardiovascular disease, but for other areas as well. Can you walk us through some of the other opportunities that you see, and obviously one being the retinal disorders as well?
Yeah, for sure. I think there's been a lot of focus on the QUELL-CV space given the ZEUS trial, but it's underappreciated how rich this biology is, right? There's a number of disease indications where an IL-1 or an IL-6 drug is either approved or moves the approvable endpoint, and we sit upstream of that, right? We have the opportunity to hit multiple inflammatory cytokines at once, as well as pyroptosis. One, the other indication that we're really excited about, where we're running a big phase II now, is in diabetic macular edema, and this is really part of our strategy about retinal inflammation in general. I mentioned that we built our drug to be brain penetrant. It has the best brain penetrance shown so far in humans, that Kp,uu CSF of 0.7.
Our drug also gets really well into retina, so we're excited to take it to some of these inflammatory diseases. That might be a unique feature of our drug. We'll see if the other drugs get there or not. There are a number of different diseases driven by retinal inflammation, like geographic atrophy, like diabetic macular edema, and we're starting with DME for a couple reasons. One is that the IL-6 injections have moved the approvable endpoint. Kodiak and Roche have very nice efficacy data here. The PIs, physicians are starting to get pretty excited about these drugs in combination with VEGF to really improve vision in this patient population where there's a ton of unmet need. What's appealing about our drug, of course, is that instead of an injection into one or both of your eyes, it's a pill you can take once a day, right?
That hits IL-6, but also pyroptosis and other inflammatory cytokines too. What I really like about DME as well is that it's happening in the context of diabetes, right? Your body isn't just a convenient way to deliver the drug to your eye. There's potential systemic benefits as well that we're excited about.
Got it.
Importantly too, one last point is that this really unlocks a patient segment which is not treated today.
Physicians usually wait until the disease is quite severe because the intervention is severe. It is an injection into your eye, right? There are 30%-40% of patients where it is more watch and wait, where a well-tolerated oral would be very appealing.
Okay. In terms of the design of the study, the patients recruited, what exactly are we going to be looking for in the DME study?
Yeah. This is 180 patients overall. We have power to show a four-letter improvement, which would be very clinically meaningful, either as a monotherapy or on top of VEGF. We have three different groups right now. We have our drug by itself, BGE-102 by itself, VEGF by itself. This is the standard of care, as well as the combination. The combination is where people are looking at IL-6, right? Because it's another injection, but we also are excited about the monotherapy because for a couple of reasons, right? It should be able to do more than IL-6, but also it should be able to access that patient population where the VEGFs are not going today.
And maybe just help bridge folks from sort of the Kodiak and Roche data to how NLRP3 could be relevant, just more mechanistically.
Yeah. Roche and Kodiak are just pure, basically IL-6 drugs, right? Which is one of the inflammatory cytokines where you see a really potent reduction with NLRP3. So we should be able to capture that effect. But pyroptosis is also very much implicated in the pathology here of DME, and that's like a sort of a separate mechanism, like IL-18, et cetera, by which NLRP3 should be able to have efficacy as well.
Okay. Super interesting. And just the timing of those data?
Yeah. So that will be in the back half of next year.
Okay.
Yeah. One important point too, when we originally conceived of this study, it was originally going to be a biomarker study, but we decided to power it up, make it a true efficacy study, and because we are looking at the approvable endpoint, we could potentially go into a pivotal study after this reads out next year. So we are really excited about this data. As we touched on at the very beginning too, this is unlocking not only DME, but also retinal inflammation more broadly. There is a lot of investor interest in MEZZI, there is an orphan condition, but also geographic atrophy. The rationale is very compelling. There are really no therapies that work in terms of improving vision, and we are really excited to take the mechanism there as well.
Great. In terms of what are the next steps after QUELL-CV reads out, is that kind of watch and wait, let us see what happens with ARTEMIS, or are there subpopulations in the CV setting that could be potentially interesting?
Yeah, great question. We are certainly not going to go right into a MACE trial.
Yeah.
That is on pause for sure. That said, if ARTEMIS were to read positive, we would be able to follow pretty quickly. ARTEMIS is the one Novo trial still standing with IL-6, where the patient population is closer to the post-MI one where they saw a nice effect in CANTOS. So the less sick patient population. It is still not quite the same study design, and there is still that question about is it the right target? But contingent on positive data there, we would definitely reconsider going back into full MACE. The other interesting thing we are watching for is to see what Lilly does with the Ventyx drug. Maybe we will get some hints in the next month or so. We will see.
But from our perspective, as I mentioned, there is a whole host of indications where these downstream drugs are approved, these injectable downstream drugs are approved. So we will be selecting another peripheral indication, or we will talk about it when we have all our milestones lined up, et cetera. But we are going to be developing it for a peripheral indication where we can look at the approval endpoint in our next trial, like as a small biotech without the $600 million of MACE spent.
Yeah. In terms of other competitors and where other competitors are kind of taking their NLRP3s, what areas do you kind of view as potentially interesting?
Yeah. I mean, there is a lot to choose from here. IL-1 and IL-6 biology, again, are approved in many different indications. So our focus is really on a few things. One is where we are unique, and that is really where the eye makes sense for us. We do not even know that these other drugs get into the eye in a way to be therapeutic, so that is very unique for us, the eye and the brain. But it is also important for us to select indications where we can go it alone as a small company. And there are a few to choose from there. I mean, there are companies looking at HS, at gout, RP. There is a whole suite of promising indications, and we will communicate more once we are ready.
Got it. Let's talk about APJ. Maybe just remind us the original program and what you learned from that program in particular, and then as you advance your new program, what are you most focused on?
Yeah, for sure. As a reminder for everybody, our original program was azelaprag. This is the drug that we in-licensed from Amgen after phase I, and it targets the APJ receptor. So it mimics the effects of a peptide called apelin, which is a sort of natural circulating peptide that has been described in literature as an exerkine. It's responsive to exercise, seems to mediate some of the positive benefits of exercise. If you go for a run or a bike ride, your apelin will spike. And we showed previously that with the Amgen drug, with other drugs in this pathway, that you could do a couple of things. You could preserve muscle from muscle loss, and you could also increase weight loss in combination with an incretin, right?
We were in a phase II study with Lilly a couple years ago when their drug, the Amgen drug, ran into There were some liver issues. There were some liver enzyme elevations, which caused us to halt the program. It just wasn't an okay profile for that population, like healthier obese.
Yeah.
We went back to the drawing board, and the universal feedback we got from all the experts we spoke to, that it was structure-related toxicity. So our design goal from the beginning was to create totally different chemistry, completely unrelated to the Amgen chemistry, which is what we've done. So we're really excited to We'll roll out that dataset soon, but the plan here is really very similar. And one other thing I'll mention is that we showed in the clinic as well that with Amgen's APJ agonist, we could preserve muscle. So we did a small human experiment where you have these older people in a bed rest intervention, right? So you have older people, and the intervention is they're sitting in bed for 10 days. They're not moving the whole lower half of their body.
This very reproducibly gives you a reduction in the amount of muscle in your thigh, which you can measure a number of ways, and more fat infiltration into the thigh. We showed that we protected significantly from that with our drug. We are really excited to get back in the clinic with APJ. The potential here is really the same, right? If anything, it is even more exciting than it was a couple years ago, because the big opportunity was always, this is something you could combine with an oral incretin to increase weight loss and also improve body composition, retain more lean muscle. Now that we have seen some of these drugs get approved, like orforglipron, they are really not competitive with the injectables in terms of the amount of weight loss.
There is a really big value proposition, I think, just sort of having a combo pill that increases weight loss. Of course, there is even more and more of a focus on having that weight loss be healthy, which is another advantage we have here as well.
Yeah.
That will be following the same sort of path there.
Got it. Still on the obesity path, I guess one question is, as we work and speak with a lot of obesity companies, the feedback, especially from patients and in the work that we do, is maintenance is probably the number one area that companies are trying to crack the code. If they could enter maintenance late, they would feel like they are maybe not competing with Lilly and Novo. Is that a profile? Is that something that can be studied relatively early from your perspective?
I think the science is there, definitely, right? First of all, I will point out that it is not really competing with Lilly or Novo because it is an add-on. It is something you would take with it, right, for the weight induction regimen. But to your point, in terms of maintenance, we have shown, pre-clinically at least, that if you give apelin as a monotherapy, that reduces the amount of weight that you gain on a high-fat diet if you are a mouse. And of the weight you gain, a higher proportion is muscle. So it is also healthier weight gain. It does have a lot of potential there. Those are bigger trials, because the effects are smaller.
Yeah.
It is certainly an interesting area where the biology makes sense for us as well.
Okay. Got it. And maybe just to wrap up, in terms of from IND to data, I think you have a pretty good sense of what is possible from your azelaprag work. When would we anticipate post-IND? How quickly can we get to some answers at least?
No, that is a great question. We do not have our formal guidance yet, because I do not really like to do that until we have officially submitted our IND.
Fair.
But we're on track to do that by end of year, and then a SAD/MAD takes as long as a SAD/MAD takes.
Yeah.
And something like a bed rest proof of concept trial, where you just put people in bed for a couple of weeks and look at muscle, which is a great sort of PD trial here, that can also be pretty quick.
And is there a potential opportunity for this novel asset, just in the way that it binds to apelin, and how differentiated is it from azelaprag on all of the key positives that azelaprag could bring to the table?
Yeah. Basically, so, well, I guess we haven't sort of publicly said how potent it is, stuff like that. So I can't sort of compare it on those dimensions. It's just, actually, I think we have. Yeah. So it is highly potent.
Okay.
It is more than tenfold more potent than azelaprag.
Okay.
And very different chemistry, as I mentioned.
Yeah. So feel good about how it is positioned versus azelaprag.
Definitely. Yeah.
to deliver similar type results.
Yeah. We also, I mean, part of the design goal too, back with azelaprag, we had to have daily doses of like 300+ mg a day. So part of our design goal was also to get that a lot lower.
Okay. Just to wrap up, BioAge's cash position and just the cash runway?
Yeah. At our last update, we were just north of $350 million, which gives us runway through 2029 with all the programs we've discussed, as well as with another indication for NLRP3.
Great. Super exciting time. Thank you so much for joining us, and we'll look forward to, I guess, QUELL-CV very soon.
Coming soon.
DME is super exciting.
Thank you.
Thanks so much, Kristen.
Yeah.