Are you on? Yes. Okay. Good afternoon, everyone, and welcome to the BioAge Labs presentation. BioAge, as you know, is targeting NLRP3 to address diseases of aging and inflammation. With us today is BJ Sullivan, Chief Strategy Officer of BioAge. Why don't you come on and give us the presentation, and we'll go into Q&A.
Sounds great, and thank you for having us today. We appreciate it. Thanks to all of you who are attending in person and virtually. I am going to start off and give you a brief corporate presentation and an overview of our programs, and then we can go into Q&A. BioAge is a platform company. We are essentially harnessing the biology of human aging and using that as a lens for target discovery and targeting pathways associated with healthy aging. Our lead program is BGE-102. It's a potential best-in-class oral NLRP3 inflammasome inhibitor. We released our phase I data earlier this year, showing what we believe to be a best-in-class profile, with essentially 98% trough inhibition of IL-1β and 86% reduction of hsCRP in obese and inflamed individuals.
All of that in a convenient once-daily dosing paradigm, with placebo-like tolerability and really excellent tissue distribution, which enables us to go after diseases driven by inflammation, not only in the periphery, but also in protected compartments like the retina. With this program, we have two ongoing phase II trials. One is QUELL-CV, which is a peripheral dose-ranging study where we're looking at three doses of BGE-102 and trying to understand the relationship between those exposure as well, and a rich set of inflammatory and metabolic biomarkers, as well as MRI imaging of the liver. That's reading out at the end of this year. We also have the ongoing QUELL-DME trial, which is enrolling and is targeting data by the end of next year.
There, we're looking at NLRP3 both as a monotherapy and as a combination with anti-VEGF to see if we can improve visual acuity in these patients. We see this really as a beachhead into a broader ophthalmology strategy, which takes advantage of the fact that we really have exceptional tissue distribution, which we showed in the clinic, getting very nice levels in the CSF. Across non-clinical species, including primates, we see very high free levels in the retina. We're really leaning into this differentiated profile of our molecule. I would also say that we're planning to announce an additional indication for NLRP3 and plan to announce that once those plans are fully solidified. That's also on the horizon for that program. We're also very excited to be back in the clinic soon with APJ.
This is a target that, in our platform, is among the most highly associated with both longevity and preservation of physical function. This is a target when you combine APJ agonism with an incretin or actually any mechanism that causes weight loss due to appetite suppression. We've shown the ability to double weight loss and restore body composition back to that of lean control animals. Actually, with a first-generation compound, we were able to show in older participants at bed rest essentially full preservation of muscle size, muscle quality, and essentially muscle protein synthesis. We have two next-generation programs we're working on, an oral and a parenteral, and we're targeting IND submission by the end of this year, and that's on track, at which point we'll essentially debut the program as well as our clinical development plans.
We're very excited to be back in the clinic with APJ very shortly. I'm going to give you a brief overview of the BGE-102 program. NLRP3 is essentially an inflammasome in the body that's responsible for essentially translating sterile inflammatory signals into both cytokine production and release, IL-1β and IL-18, as well as mediating the inflammatory cell death process called pyroptosis. There are other inflammasomes in the body, but NLRP3 is really the key mediator of sterile inflammation. By that, I mean inflammatory signals that are not associated with an infection or a pathogen. This could be metabolic stress, nutrient excess, a lot of the things we associate with creating this sort of chronic simmering inflammation. Those are mediated by NLRP3. In our cohort, we see that NLRP3 activity is highly associated with mortality in humans.
BGE-102 is our lead program, and we'll get into this in more detail, but we think it has best-in-class potency with an IC90 of 1.6 nanomolar. In the clinic, we're seeing 98% suppression of IL-1β trough at the 120 milligram dose. We're getting 24 hours of essentially complete target inhibition. We feel that we're able to really inhibit this target almost completely with essentially placebo-like tolerability and a high degree of CNS penetration. We did lumbars in our phase I and showed a Kp,uu,CSF of 0.7, which we think is best in class.
I would also note here that we'll get into a little bit of the unique binding site, which we've characterized, and the IPs around that and around this molecule are out to 2045, with claims not only for the specific structures, but also broadly covering ligands that interact with this binding site. NLRP3 has been a target of interest for drug development for 20 years. The original compound that Pfizer took into the clinic was MCC950. This targeted the ATPase pocket on the molecule. To our knowledge, all of the other programs in development are essentially derivations of that structure or novel chemotypes targeting that binding site. We did a sort of a de novo approach. We did a DEL screen. We blocked that binding site, intentionally looking for novel binding sites.
We were able to characterize this with a collaboration with Matthias Geyer at the University of Bonn, and we've published on this extensively. This binding site is distinct, and what it enables is the ability to inhibit the inflammasome, both in its active and inactive form. What we see is that we're really able to completely inhibit the target. The inflammasome and NLRP3, it has a monomeric form, and then it assembles into a decamer in this really big scaffolded inflammasome assembly that is required to process the cytokines and initiate pyroptosis. Once that complex assembles, it appears that the original binding site is blocked. We think that this binding site may, in part, explain why we're able to achieve the depth of target inhibition that we've shown in the clinic.
To go over our phase I results, these are the results that we shared in April of this year. This included essentially a standard SAD/MAD with healthy volunteers, and we also included two cohorts of obese and inflamed individuals. Essentially, this was informed by the Ventyx trial, which had read out and essentially showed that in patients, some similar patients, you basically achieve maximum biomarker reductions within a couple weeks. We think the goal was to show, okay, what is the depth of the biomarker reductions that you're able to achieve, with the expectation that we'll be able to sustain those over chronic dosing? The highlights here are basically, safety tolerability was really placebo-like, excellent, and across the phase I. Nice dose proportionality with clearly supporting once-daily dosing.
From a biomarker and pharmacodynamic perspective, again, we were able to achieve essentially 24 hours of complete target inhibition. In both of the doses we tested in these obese and inflamed individuals, we were able to achieve an 86% reduction in CRP. I'm just going to walk you through some of the key findings here. This is the CSF PK from lumbar punctures in healthy individuals, and you can see that this is basically a steady state level at the 60 milligram QD dose. We were able to achieve essentially IC90 coverage in the CSF, which rose to about 3X the IC90 at the 120 milligram dose. Very nice tissue distribution into the CSF. This is essentially showing the magnitude of target inhibition.
This is an ex vivo stimulation of blood from these patients, healthy volunteers, 60 and 120 milligrams QD, and we're basically able to show up to 98% suppression of the target. This basically tells you the same thing, but I think it illustrates it in a very visual way. You can just see here, this is the 120 milligram dose group at day one, day eight, and day 14. What we're able to show is that by day eight, you're basically getting 24 hours of complete target inhibition, right? We're really knocking the target down for that full 24-hour period. This is one slide just summarizing the data from the obese inflamed MAD cohorts. You can see here in the 60 milligram and the 120 milligram MAD cohorts, we were able to achieve an 86% reduction in CRP.
As we go into the QUELL-CV trial, the dose-ranging trial that is reading out at the end of this year, one of the goals of that is to really understand what is the dose response relationship between BGE-102 and then these metabolic and inflammatory biomarkers. You may not need to have 98% trough inhibition of IL-1β to have maximal effect on some of these downstream markers. That is one of the key goals of the ongoing study. To briefly touch on therapeutic areas, we think we have the ability to address inflammation very broadly across compartments. Not only do we think we have potential best-in-class performances for an NLRP3 inhibitor full stop, but because we have demonstrated very high penetration into the CSF, we think obviously that that compartment is highly addressable.
Across non-clinical species we have looked at, including primates, we see excellent exposure in the retina. That is obviously one of the anchor therapeutic areas for us as well. We think we are able to address inflammation broadly regardless of the compartment. This is the design of the QUELL-CV trial, which is currently ongoing and going to read out at the end of the year. It is dose-ranging. We are looking at three doses of BGE-102 and placebo, so we are looking at 30, 60, and 90 milligrams QD. 90 milligrams essentially is the PK equivalent at steady state to the 120 milligram dose we tested in phase I, where we expect similar 98% trough suppression of IL-1β.
We expect 60 and 30 milligrams are going to give us lower levels of IL-1β suppression, and so we are trying to interrogate really, again, the dose response and relationship to downstream markers like CRP, which is the primary endpoint, as well as a variety of other inflammatory and metabolic markers that we are looking at. We will also be looking at MRI imaging of the liver, so we will look at liver fat as well as liver inflammation, which Ventyx showed a benefit in their three-month trial. We will be able to look at a much richer set of these markers and looking at markers that take longer to change than would have been feasible to measure in the context of the phase I. This broadly supports cardiometabolic indications.
We will be able to really look at this rich set of data to understand where within the cardiometabolic space this drug might play. To touch on hsCRP as the primary endpoint, we think it is a very important PD marker to help us understand and benchmark the anti-inflammatory activity of the molecule. I think the elephant in the room is ZEUS, and how do we interpret those results? I think what we can glean from that is it is certainly not a surrogate marker for cardiovascular benefit. But we still think it is a very strong PD marker. This slide really essentially illustrates how both pathways converge on CRP. NLRP3 inhibition really happens at the level of the plaque, in the context of cardiovascular disease where cholesterol crystals or oxidized LDL, other inflammatory stimuli stimulate NLRP3.
It secretes IL-1β, which is a local cytokine, and that sort of ultimately translates into this sort of systemic alarm signal of IL-6. That converges on CRP, as well as just blocking much further downstream and just blocking IL-6 directly. Both of those can similarly impact CRP, despite capturing very different biology, if that makes sense. In looking at the ZEUS results, in our view, it actually really strongly points to NLRP3 being a good target here. It is much further upstream if you think about what has worked in inflammation. Colchicine, certainly, IL-1β in the CANTOS trial. If you harmonize that and reconcile it with ZEUS, it really, in our view, seems to point upstream, much more so than it being the other hypothesis that maybe the patients were too sick or was too far gone.
The fact that there was sort of no subgroup signal in the full ZEUS data, in our view, seems to strongly suggest it is actually the upstream biology that may be more relevant for cardiovascular disease. That said, as a company, this is not a priority for us. I think we are shifting in other directions, and we are really leaning into our ophthalmology program, and again, can announce an additional indication for the program at a later date. I think the key message here for us is that it is on pause.
It is no longer a priority. That said, we have done a lot of preparatory work from a CMC perspective and sort of planning for phase III enablement. If there is a surprise, for example, in Q1, and ARTEMIS, the other Novo trial, reads out in the acute MI setting, we are ready to respond to new information very quickly.
Just to sort of close out on cardiometabolic, obviously, atherosclerotic disease is an area where we think NLRP3 is very relevant. There are a number of other facets of cardiometabolic disease, including insulin resistance, MASH, kidney disease, where NLRP3 may be relevant, and we will be able to sort of interrogate the rich data set that we are generating in the QUELL-CV trial to understand where this may play. Ophthalmology is our other sort of anchor therapeutic area for BGE-102. We think that this is an incredibly attractive target for ophthalmology, not only with the potential to deliver a novel mechanism of action, but also very importantly for patients, reducing the treatment burden, which can really There is a huge disconnect between, I think, clinical trial treatment outcomes and real-world outcomes, and a big part of this is sort of patient willingness to undergo treatment.
This also enables us to treat both eyes simultaneously. A lot of patients who have retinal disease have bilateral involvement, which means often two injections and two visits. Again, a huge value proposition in streamlining care for patients. I think also, importantly for us, this presents the opportunity to address both the local retinal inflammation as well as the upstream drivers of disease. In DME, for example, we know that NLRP3 is involved and may have benefit for this sort of metabolic syndrome broadly. You are able to potentially address and improve the underlying disease and sort of the key risk factor for DME, as well as addressing the specific local inflammatory biology. Just briefly, DME and GA are sort of the two priority indications for us. We also think this is highly relevant in MEsi and UME.
DME, this is sort of a leading cause of vision loss in younger individuals, so less than sort of 65 years of age. The key risk factor is obviously hyperglycemia and diabetes. The way it is treated right now is really focused on anti-VEGF, and steroids and laser for more recalcitrant disease. The goal here is really to reduce the injection burden. There are a number of patient segments we think are highly addressable here, one being the 40% that are in this, quote unquote, "watch and wait," who are, their maculas are wet, but they don't have sufficiently compromised vision to initiate intravitreal therapy, or they just don't want to. On the other end of the spectrum, there are patients who are on VEGF therapy, but having incomplete disease control.
We'll be able to interrogate both of those patient segments really in the ongoing QUELL-DME trial. I'm going to skip GA just for the interest of time, but the inspiration for the QUELL-DME trial was we're being The high-level motivation is really the IL-6 experience, and if you think about the Roche, the vamikibart program, they were able to show essentially a line of BCVA improvement in two treatment settings. So one is a monotherapy, as well as in combination with VEGF. And they were able to show that relatively quickly. So they were able to show sort of maximum separation of the groups in about a month or two. Regardless of intervention point and within a relatively short period of time, they've demonstrated that an anti-inflammatory can have benefits in visual acuity.
That at a high level inspired the design of QUELL-DME, but I would point to important distinctions and differences in the biology of NLRP3. So it's much further upstream, and so you're capturing IL-1β, IL-18, as well as pyroptosis, which affects and compromises the microvasculature in the retina. So, there's a lot more biology here than just IL-6. Our preclinical models certainly support strong potential benefits in this indication. So, this is a diabetic retinopathy model, and so you can see in the mice when you treat with BGE-102 orally, you're able to essentially completely rescue retinal vascular permeability. So this is just fluorescein angiography and measuring leakage into the retina. And then on the right, this is sort of zooming in and looking at the integrity of the microvasculature.
So both on the left, it's really the macro, on the right, it's really the micro, but you're able to almost completely correct this phenotype with BGE-102 monotherapy. So this is the design of the QUELL-DME phase II trial. So we're looking at center-involved DME, and these are either naive or washed-out patients. We're looking at essentially two comparisons. One is monotherapy to its baseline, and then we're also comparing VEGF to VEGF plus BGE-102. So those are the key comparisons. We're powered for essentially a four-letter improvement in both of those comparisons. And again, the primary endpoint is visual acuity. We'll obviously be looking at a variety of exploratory markers, including retinal parameters, as well as sort of systemic biomarkers to really try to understand the full picture in these patients.
In terms of the goals of the study, obviously first and foremost, we want to demonstrate a benefit in visual acuity, but we also see this trial as essentially a beachhead into ophthalmology more generally. As I mentioned, there are other highly addressable indications like GA, Messi, and UME, which could follow on from this trial with a clear demonstration of pharmacodynamics and target engagement in the eye. This trial is going to read out at the end of next year. I will briefly touch on this. This is a model of geographic atrophy, which again, is a high-priority indication for us. There is a robust literature here showing that essentially NLRP3 knockout in mice can prevent the rapid and profound degradation of the retinal pigment epithelium. We are able to essentially recapitulate that with oral delivery of a BGE-102 analog.
We think we are able to access the retina and really prevent this tissue deterioration that is triggered by cellular debris, essentially in the retina, lipofuscin and drusen, which are the hallmarks of the disease and highly pro-inflammatory. This is another naturally aged model, which we think is really exciting. We have an outbred mouse strain in our lab, which we have developed to study natural aging processes. On the left, this is really just a characterization of the model, which is, you get an AMD phenotype over time, and with age, you get essentially deposition of lipofuscin granules in the retina. When we treat with a BGE-102 analog, we are essentially able to completely prevent further accumulation of that lipofuscin. That is another high-priority indication for BGE-102 and one we would certainly be interested in exploring after establishing clear pharmacodynamics in the eye and QUELL-DME.
There is also interesting human data to support this hypothesis as well in GA. Inflammasome Therapeutics, for example, they are running a pilot trial right now with an NRTI that they are delivering as an implant to deliver high concentration in the retina. In some of their early data, they have shown slowing of lesion size in excess of 50%, which compares very favorably to the complement inhibitors right now, which showed approximately 15% slowing of lesion size growth in their pivotal trials. We think that this is early data, but certainly very supportive and very exciting in our view. I will touch quickly on APJ. This is the target we are very excited to be back in the clinic with this year, or rather at the beginning of next year.
Apelin, which is the ligand for APJ, it is one of the strongest signals in our platform associated with longevity as well as the preservation of physical function, and is associated with a whole variety of cardiometabolic benefits on a proteomic level. We show preclinically that when you combine APJ agonism with an incretin, you can essentially double weight loss as well as completely restore body composition to that of lean controls. With our first-generation APJ agonist, which we licensed from Amgen, we were able to demonstrate essentially complete preservation of muscle size, muscle quality, as well as muscle protein synthesis in older individuals at bed rest as a proof of principle of this muscle-preserving activity. We just reported a cash balance of just over $350 million in the last quarter, and that essentially funds all of the activities that you see here.
QUELL-CV reading out at the end of this year, QUELL-DME reading out at the end of next year. It also funds an additional indication for BGE-102 through proof of concept, and that is to be announced. It also funds APJ programs through proof of concept. The next milestone here is IND submission by the end of the year. At that point, we are excited to announce, essentially debut the program, as well as share clinical development plans for that program. We are very excited to be back in the clinic with APJ very shortly. That is it. I am happy to take questions.
Okay, great. I am going to ask you one question about the cardiovascular indication. What do you need to see from ARTEMIS to give you confidence that you can move forward in that indication, or whether it is worth moving forward in that indication?
Yeah, I mean, it is like a clear signal. I think, whether it is stat sig or just a magnitude that is decisive, right? I mean, I think that if it is gray area or you think that there is some benefit and NLRP3 might be stronger, I think we are very excited about the plans. We had the studies we have ongoing and some plans we are yet to announce. I think it would have to be a very decisive win in order to sort of change our tune on ASCVD.
Would you say that ARTEMIS has the most similar patient population to what you are looking at in the Quell study?
It's a little bit different. The QUELL-CV study is sort of a it's obese individuals, cardiovascular risk, elevated inflammation. The acute MI patients are like hyperinflammatory, so this is right after an event. It's not that dissimilar from the CANTOS trial where the IL-1β was studied and did show a very meaningful benefit. But each population is a little bit different. I think we don't want to overread at this point. We would be delighted if there were a surprise to the upside and there were a huge benefit in these patients, and it really was that it was the wrong population in ZEUS.
I'm a little bit skeptical just because none of the subgroups in ZEUS moved. The idea that this group was too far gone, you didn't see any sort of directional benefit in higher eGFR patients, for example. I'm skeptical, but would be delighted to be surprised.
Okay. All right. I'll leave it at that. Okay, DME now. Maybe you can talk to us about the patient population that you specifically want to go after in DME. Obviously, anti-VEGFs work pretty nicely, but-
Yeah
not everyone is getting treated. Are you looking for that earlier patient population?
I think that is an incredibly attractive population. This is essentially 40% of patients are in the watch and wait category where they have edema in the eye, but don't have sufficiently compromised vision or they don't want therapy. When you speak to investigators and sites, these are patients who are working. It's a huge inconvenience. No one wants to get a needle in the eye. I think everyone appreciates that an oral here would be an incredible unlock for these patients. That is a very attractive opportunity, and we're obviously looking at that in the monotherapy group. Otherwise, even on top of VEGF, if it can give you better disease control between doses or it can improve disease control for patients who are refractory, that's sort of the highly inflammatory phenotype, right, of those refractory patients.
We're trying to understand in this trial the benefit in those different treatment settings.
Would you say that DME has more of an inflammatory component, or is it dependent on VEGF? Because obviously, VEGFs have been developed here, but how much of this disease is driven more by the inflammatory cascade behind the disease?
Yeah, I mean, it is a highly inflammatory disease, and so hyperglycemia is an inflammatory stimulus, right? It's one of the classic activators of NLRP3, the metabolic stress that results from it. We think that there's multiple aspects in which inflammation, in this sense, can contribute to the DME pathology. It's not just through the cytokine cascade, although IL-1β directly induces VEGF. You do certainly get that pro-inflammatory classical milieu, but you're also getting that, like, at the level of the endothelium, you're getting this sort of compromised integrity of these cells because you're getting this pyroptotic cell death, right, that further contributes to the edema and the essentially the lack of tissue integrity in the retina.
Okay. Just you mentioned earlier that obviously this is you're dealing with a diabetic population, so they have a whole host of things going on. Are there any other biomarkers that you're looking at beyond just the eye to look at how it might be impacting the rest of their disease?
Absolutely. This is a huge thing. I mean, in terms of just the glucose control, kidney function, the whole range of cardiometabolic comorbidities, right, with type 2 diabetes, we're going to be looking at, and the standard set of systemic labs that accompany this. I think it's a huge part of the value proposition in addition to a new mechanism, in addition to being oral, but the ability to actually address systemic cardiometabolic disease as well at the same time, I think is incredibly important to that.
You're looking at metabolic markers just as a secondary exploratory?
Totally, yeah.
Okay. On the arm that is monotherapy, we are looking at earlier stages of disease.
What are you actually measuring there? Is it going to be harder to show any kind of separation? Are you measuring progression to DME or first vision-threatening event, or what is it that you are measuring?
Yeah, so in all of the groups, the primary endpoint is visual acuity, right?
While these are treatment-naive patients or washed-out patients, we are looking for those who do have sufficiently compromised vision that we can show a benefit, right? So these are not patients who are a little bit wet, but their vision is intact. We do need to have the eligibility requires some compromise in vision so we can show a benefit.
Okay. You mentioned that you had started enrolling your first patient.
Yes.
How is that going? I know it's really early, but
No, it's going well. We're off to the races.
It's maybe easier to enroll a patient when you're offering them an oral than needles in the eye, so I'm hoping maybe that'll speed things up.
Yeah. We are maintaining our guidance for top line at the end of next year.
Okay. All right. Well, great. Thank you very much.
Thank you very much.
That was great.
Appreciate you having us.
Yep.