Good day, everyone. Welcome to day three of Cantor's Global Healthcare Conference. My name is Prakhar Agrawal. I am a Biotech Analyst at Cantor, and for our next session, we are very excited to host BioAge Labs. From BioAge, we have Kristen Fortney, CEO. Kristen, thank you so much for joining us.
Yeah, thanks for having me today.
Great. Maybe we can start off with a quick overview of the company, the pipeline, and some of the key priorities for you over the next 12-18 months.
Yeah, for sure. At BioAge, basically, we have a platform that helps us identify promising targets for metabolic health and longevity. Our lead program is BGE-102. It is a potential best-in-class NLRP3 inhibitor. We showed earlier this year in our full phase I data set that we have potential best-in-class brain penetration, IL-1β suppression, as well as CRP reduction. That drug is currently in two different phase II trials. A trial focused on cardiovascular results, which we will speak to later with the ZEUS results and everything and what that means for us. We also announced earlier this week that we have also advanced that same drug into a phase II trial for diabetic macular edema with a phase II efficacy readout coming in the second half of next year. It is a really exciting area for these therapies.
We also have an apelin agonist program and are on track for our first IND filing at the end of this year. Those are the closest milestones.
Great. Maybe we can get the elephant out of the room in terms of Novo's ZEUS dataset. What is your take on that, and what does it mean for NLRP3?
Yeah, no. For us and for everybody else, especially for patients, it was really disappointing to see that IL-6 failed to move MACE outcomes in the ZEUS trial, right? That initially was an important area of focus for us. We were getting ready to go, potentially, into a phase III ASCVD trial as early as next year. That is really on pause for us now. That was a challenging indication for a small biotech, even if ZEUS had been wildly successful, right? Mostly because it is capital intensive. Frankly, if it were not that capital intensive, if it were a $20 million or $50 million bet, we would still go for it because the biology is different and we can get to that.
As for ZEUS itself, there are still two different potential explanations that we are waiting for more data to learn which of those it was, whether it is a patient population question or a target question, right? Because the history of this field, there is precedent with IL-1β in the CANTOS trial, where that led to very robust MACE benefits, 15% in the whole population, up to 25% if you look at patients with low CRP. That just failed to translate entirely, right? That was a milder patient population. The ZEUS population, as people have discussed, include patients with quite severe kidney disease. Potentially, we will know more when we learn, hopefully, at AHA, potentially there were a lot of events in that trial not related to heart inflammation, right?
The good news there is the one trial Novo hasn't stopped yet is ARTEMIS, which is a post-MI population. We will get a look at what this mechanism does in that population as well. But the other potential explanation is that this is the wrong target, that we need to look further upstream. What we know is that IL-1β seems to work, and IL-6, of course, doesn't impact IL-1β. NLRP3 does. It's the canonical marker. In phase I, you look for IL-1β suppression to see how your NLRP3 drug is doing. So it might be too downstream to have the effects that you need in cardiovascular disease.
Okay.
Oh, I will mention briefly, there's even a couple of strategics are very open about that. Novo themselves have said so, that NLRP3 specifically is a very promising mechanism here, and IL-6 could be too far downstream. Yeah.
Okay. So maybe when Novo presents the detailed data, anything that you will be watching closely in terms of markers that maybe an NLRP3 mechanism could capture, which an IL-6 antibody could not, given its downstream mechanism?
Yeah. The most interesting information of that trial, I am going to guess, is going to be related to different patient subsets, whether they can separate the severe from the less severe and see anything different. That said, given the hazard ratio was so close to one, we are not holding out a ton of hope, but we would love to see anything they find there.
Okay. In terms of the population, you mentioned about the severity. I guess the heart failure trial, the post-MI trial is still ongoing. Why should, theoretically, that should have positive implications as well, if there is any?
Yeah, for sure. The reason people are still holding out some hope for that trial is because it's a closer population in terms of the post-MI, the milder disease, to the CANTOS trial population where the IL-1β mechanism worked.
Okay.
There, hopefully, the events are really driven by cardiovascular disease as opposed to kidney issues.
Got it. You still have BGE-102. There are still, as you said, many NLRP3s that other companies are working on. Maybe at a high level, how is BGE-102 differentiated versus the competitors?
Yeah, for sure. I think it's worth pointing out, right, the focus has been on cardiovascular disease for good reason. There's arguably even more patient need now than there was a month ago. It's a challenging indication because of the price tag on the really pivotal trials. There are many different indications where there's an IL-6 mechanism or an IL-1 mechanism approved, right? The prospect of an oral therapy that does the same or better, so hitting multiple cytokines is really promising, right? I think there's still a lot of focus on this class, and we're going to explore, as a field, what the best indications here are. We're doing DME. We're going to pick another indication soon, so more on that one later. To your point, in the space of NLRP3s, we have best-in-class brain penetration, so our Kp,uu,csf is 0.7.
We think it's really important to suppress neuroinflammation in the brain and also in the eye. That's really what motivated some of our ocular indications. We don't know if the other drugs are getting insufficient concentration in the eye to have an impact on these retinal inflammatory diseases. We focused in the past, of course, on the best-in-class CRP reductions. That's less of a focus now because what we've learned from ZEUS, if anything, is that CRP alone is not enough for a MACE benefit. We also have best-in-class IL-1β reductions. We showed, for example, in our phase I that the 60 mg once-a-day dose gives you IC90 coverage for 24 hours, but our higher dose actually gave you 98% IL-1β reduction, which no other drug has shown.
Right. Maybe if you can walk us through some of the data, both on hs-CRP as well as IL-1β. What did you show in humans, and how did it compare with some of the other NLRP3s like Ventyx and NodThera, and maybe some others as well?
Yeah, for sure. Ventyx, the dose they took forward was basically an IC90 dose for IL-1β. That was sort of the maximal level they showed in the clinic. As I mentioned, showed up to 98%. The CRP reductions that they showed after three months of treatment in an obese inflamed population were about a 70-something percent reduction, and we, in contrast, showed an 86% reduction at a shorter trial. This is a three-week trial, and we have our three-month sort of ongoing trial right now, which will be the closer comp to Ventyx, so stronger on those lines. NodThera, the main differentiator is that that's a sort of a twice-a-day large dose, and this is a once-a-day sub 100 mg dose.
Got it. In terms of the safety, just remind us about the mechanism, like NLRP3 versus IL-6. What safety differentiation would you expect?
Yeah. There is a theoretical safety advantage versus an IL-6 over an IL-1. We have seen with IL-6 and IL-1 antibodies that there can be a small, but it is there, risk of serious infection. Of course, like an antibody is a very blunt instrument. It is turning its inflammatory cytokines off all the time under all conditions. In contrast with NLRP3, there are parallel inflammasomes that can be infection responsive and that can sort of ramp up cytokine productions in response to a threat. So there should be an edge there, yeah.
Okay.
So far these have been in up to three months, I guess, in different studies, and they have a pretty clean profile. Yeah.
Got it. You have the phase II QUELL-CV trial ongoing. Just remind us what are you testing there, and what are you hoping to see?
Yeah. In the QUELL-CV trial, and this was really originally designed to inform our phase III ASCVD trial next year. It will still be useful for that if we see a positive ARTEMIS or something else happens in the space. I would like to point out now that it teaches us a lot more than just about CV. We are not going into a cardiovascular population for that trial. It is about 160 people. There are three different doses of our drug, BGE-102, as well as a placebo group taken once a day for three months. It is an obese inflamed population. These are people that are increased risk of diabetes, MASH, cardiovascular disease, like all sorts of things. So two important points. It will be the right dose selection trial for any peripheral indication we take forward, and we will communicate another one of those soon.
It will basically tell us which of these doses gives us the maximal NLRP3 pathway induction. We are also looking at a very rich set of biomarkers that are relevant to multiple different diseases. For example, Ventyx saw that really nice liver inflammation signal with MRI. We are looking at that as well. Yeah.
Got it. Assuming this is positive, I think the timing is end of the year.
Yes.
Assuming this is positive, I guess the CV outcomes trials would be on pause, but what about other CV indications? I think one of your competitors announced like peripheral arterial disease as one of the indications that they are going after. Is that something of interest or other indications?
Yeah. We think this has promise in a lot of other related indications. We discussed some of the other ones that can happen in the obese context. There's PAD, as you mentioned. Our intent is to select another indication and communicate that in the next few months, but we're not quite ready to talk about it yet.
Okay.
Yeah.
You're also testing BGE-102 in retinal diseases.
Yeah, that's right.
Maybe just talk about the rationale to go after these indications.
Yeah, for sure. No, we're really excited about the application of the inflammasome in multiple different inflammatory diseases of the retina, which includes DME, which is where we're doing our first trial, but also geographic atrophy is really exciting. There's a lot of evidence here, both in humans as well as in animals, that this could be a really important pathway in those diseases. In the context of DME, for example, basically the NLRP3 signaling can drive the vascular leakage in DME, and we already know from human data that this is a case, a different example, where an IL-6 drug can move what is the approvable endpoint, which is BCVA. Roche and Kodiak Sciences both have programs here where it's an IL-6, usually combined with a VEGF, where they've shown significant clinically meaningful vision improvements. The rationale for NLRP3 is that, again, we're an upstream node.
IL-6 is not the only relevant inflammatory cytokine in any of these diseases. There's also a role for IL-1. There's also a very well-documented role for pyroptosis in IL-18. So you can hit all of those with the same target, and that's sort of even ignoring the fact that this is also an oral medicine. What we're really excited about, to speak about DME specifically, so that's the trial that we just kicked off this week. It's 180 patients. It's powered for a four-letter BCVA improvement, and we'll see that in the back half of next year. We're looking at basically our drug as a monotherapy, VEGF as a monotherapy, as well as the combination. What's important, too, as you think about this as an oral therapy for DME, is that there's these different patient segments that might have different benefits.
Because these people right now are getting VEGF eye injections into the eye. For that reason, 40% of patients are not treated, like they're sort of in this watch and wait period because the doctors wait until you're really losing vision before you start to get these eye injections because it is so invasive. So an oral, we've been told that that has an improvement, even less improvement than a VEGF would be really appealing there, right? Then, of course, there's a whole group of patients as well who are not very well responsive to VEGF, in which case you're taken off that because, again, it's very invasive. Then there's the third category, the people who are responding well to VEGF, and as we've already seen with IL-6, there's a meaningful benefit with the two of them together.
So we think we could meet or even exceed that with NLRP3 when we're hitting multiple inflammatory cytokines. So we're really excited to see that. That's just the D. I should mention, too, right, DME is, of course, happening in the context of diabetes.
Right.
Your body is not just a convenient way to get to the eye, there could also be systemic benefits to this mechanism, right? We are going to look peripherally as well. We will be able to see the benefits to the diabetic patient as well. Beyond DME, geographic atrophy is really promising. That is a longer trial, so we had it sort of second in line, but we think the science and the mechanism is really promising there, too. That is an example where there is, again, sort of abundant preclinical evidence, a lot of commercial white space, in addition to the usual geographic atrophy preclinical models, which are in our corporate presentation. We actually developed our own, because the other, the ones in the literature, they are all these acute insults and how translational is that, really?
We actually have large colonies of naturally aged animals and really old mice that get these eye, basically junk in their eye, right? That leads to an AMD-like phenotype, just like we do. We saw a very profound protective effect with this drug, so we are pretty excited about that, what we think is a more natural model. Of course, there is also the small human experiment from the private company, Inflammasome Therapeutics.
They have an ocular implant that inhibits the inflammasome, and they have shown very nice sort of lesion size reduction, much superior to complement from a small cohort of patients, but very promising initial data.
Got it. Great. Maybe on the, I guess for a drug like this and retinal diseases, the retinal penetration will be supremely important. How much drug are you getting into the eye, and how much do you actually need?
Yeah, no, that's a great question. We're using the 90 mg dose in our current phase II. It's to make sure that we have IC90 coverage in the eye. We've looked so far in multiple species, including primates, including rabbits, including mice, and we get therapeutic levels in the eye. We also, in our animal models, which are in our presentation, those very same doses that produce the maximal effect peripherally also produce the maximal effect in the eye, where they completely correct, whether it's the vascular leakage or whatever we're looking at in the model. There's certainly preclinically, there's abundant drug in the eye. Then in humans, the best evidence so far is the brain penetration. The blood-brain barrier and the blood-retina barrier are quite similar. Usually, when you get into one, you get into the other.
As I mentioned, our Kp,uu,csf is 0.7, so given all that evidence, we think there'll be plenty in the eye.
Okay. You did make changes to the DME trial earlier this week, going from a biomarker to more BCVA. Maybe just walk us through the decision-making process there to change that.
Yeah, for sure. Initially, we were doing a first look just to look at IL-6 target engagement and then to sort of unlock multiple indications. But we decided it was smarter to make it into a true efficacy trial. It pulls in the timelines hugely, right? Now we're going to have a meaningful endpoint, which was, I think we got a lot of feedback that okay, you're going to move IL-6 next year, but what does that mean? How exciting is that? So, we ramped up the power so that we could actually see a meaningful benefit in BCVA, and that means that we could go into a pivotal trial afterwards. It really pulls in the timelines for the whole DME path.
We're still going to look at the intraocular biomarkers, IL-6, which is relevant to some of the other indications we can go after, but this really accelerates our path to approval, potential approval in the eye.
Got it. In terms of the different arms, given you have the VEGF arm as well, the combination as well as BGE-102 as well, maybe first of all, what's clinically meaningful in terms of differences on BCVA?
Yeah. We're powered for basically a four-letter improvement, which would be clinically meaningful, either as a monotherapy or on top of a VEGF.
Got it. Got it. What about some of the other key secondary endpoints that you will look at that would be relevant?
Yeah. We'll look at CST as well. IL-6 didn't move that quite as much, but this might be different for this mechanism, right. The BCVA is, of course, the most meaningful. We're going to look at the biomarkers that we can, right, because this is aqueous taps, so unlike in the blood, it's a very small volume of fluid. IL-6 is top of the list, and we'll try to look at other biomarkers if we can.
Okay. Got it. Remind us about the duration of the trial, and is it long enough to show optimal efficacy, or would you be able to show that in a more longer trial?
Yeah. This is a three-month trial, and historically, for IL-6 and for other agents, too, you see about 80%-90% of the improvement in even after two months, and then it kind of plateaus outward. So it's just a really good window for us to see the effect quickly. Yeah.
Okay. Got it. The next steps for this program would be a pivotal in DME if the-
That's right.
Okay.
Yeah.
Got it. You talked about briefly on how the product could fit in the DME landscape, but maybe just talk about the monotherapy as well as the combo approach in a little bit more detail.
Yeah. The monotherapy can really address some of these patient segments that don't have any treatment right now, which is a lot of patients, right? Especially, I think the 40% watchful waiting category, where you know the disease is progressing, but where it's not severe enough to start to get these injections into your eye. So it really sort of unlocks that category. There's also, of course, those people who aren't responsive to VEGF, which is another large segment of the population. I should say too, so VEGF, there is some preclinical drying with the monotherapy as well. So VEGF is also part of the NLRP3 pathway. So we're also interested to see if the mono behaves like the combo. That doesn't have to be very exciting.
Right.
But there is that potential from the biology.
Got it. You mentioned about MESI as well. I think that's a super interesting indication which a lot of people don't know about. So maybe, what is MESI?
Yeah. That's just sort of a bit like a subset kind of disease. Like a rare disease, rare kind of inflammation, again, driven by NLRP3. So here we're probably going to be following the data of others. There's a readout from, I think it's Kodiak coming soon.
Yeah.
We'll wait and see there. I would probably say the most excited about geographic atrophy next, but MESI is also interesting. Yeah.
But if, let's say Kodiak's data is positive in MESI, could you, given it's a little bit of a different trial population and maybe the pricing could be different as well, given the size of the population, could you go after MESI as well with maybe this NLRP3 or maybe some other compound that you may have?
Yeah, that's a great question. We do have another NLRP3 we will be talking about soon, where it's too early to give clinical guidance. We didn't touch on this earlier, but we have a novel binding site to NLRP3. We have very new chemistry. We wanted to have a portfolio of differentiated NLRP3s. Part of the idea for that is that we do believe these are going to be relevant in multiple indications, and we want to have ways to go after more than one with more than one molecule. More on that later. Yes, there might, depending on the indication and the pricing strategy, that might make sense for multiple molecules.
Got it. GA, I guess, is there any data set that you are looking in the near term that will help you make the decision on whether to move forward or not? Maybe just talk about the plans there.
Yeah. No one's really testing anything very like this, with the one exception of that private company I mentioned.
Yeah.
Inflammasome Therapeutics, and they had released some of their data in January this year, and they released more over the summer. So far so good. We think that's already quite promising. That's of course, total commercial white space. The complement inhibitors do not seem to improve vision, seem to improve the lesion size a little bit. We think there's a lot of opportunity to do better, and we think this is an exciting mechanism there.
Right. Did the private company show improvements in vision as well?
They showed a small improvement in vision as well. Yeah.
Okay.
Again, small data set, but.
Yeah.
Very intriguing. Yeah.
Got it. Interesting. The company originally went IPO on the apelin target. Maybe just remind us about where you are in terms of apelin.
Yeah. We are going to be back with apelin pretty soon. Our guidance is IND filing at end of year. At that point in time is when we will give guidance for clinical readouts. This is a target we are really excited about. Again, it has got a great signal in our human data, same as with NLRP3, and it is a target linked to physical function and metabolic health. What we showed with our prior apelin, we took it into a phase I muscle atrophy trial. This was a bed rest design where older people sat in bed and did not move the lower half of their body for a 10-day period, which leads to measurable muscle atrophy in the thigh. We saw a significant protective effect with our earlier APJ agonist. That is like a really nice PD, POC. This is a human muscle target.
Pre-clinically, when you combine an APJ agonist together with an incretin drug or any appetite-suppressing mechanism, which will have a similar effect on your metabolism, we saw additive weight loss as well as improved body composition. We are really excited about the value prospect there. We are working on both oral and injectable APJ agonists. The value proposition is a bit different for each. On the oral side, what we believed a couple of years ago, and what is still true today, is that those drugs like orforglipron, like oral Wegovy, they are not giving you injectable-like weight loss. They are not matching them. If you had a combination pill of your incretin together with another mechanism, like an APJ agonist, that gave you tirzepatide-like weight loss or a bit more weight loss, that would be the category winner. That is already exciting on its own.
We think that there is also the body composition is important, too. On the injectable side, we probably already have all the weight loss we need, but especially in older populations, you really want to preserve what muscle you have.
Got it. Remind us about how these oral, maybe on the oral side first, how this is different from your first gen compound. What changes did you make?
Yeah, for sure. The first gen compound that we had was a drug called azelaprag, which we in-licensed from Amgen, and it had some structure-related liver tox that we saw after a couple of months. This is a totally different material, whether it is the oral or the small molecule, like zero similarity in terms of the chemical scaffold.
Okay. How much of the, I guess, liver safety can you de-risk pre-clinically, and maybe just talk about that?
Well, unfortunately for azelaprag, you couldn't.
Yeah.
Because Amgen had done nine-month chronic tox, as well as 21 days of dosing in humans and did not see it, because it just took a couple of months to happen in the human. But again, it is related to the structure from the experts we spoke to, and it is a different structure, so we think that risk should not be there.
Okay. As we think about the development path for apelin, which population will you go after first, and is the subcut also in the same timeframe as oral?
Well, what we guided to was first IND end of year. We did not say which one.
Yeah.
They are not too far away from each other.
Okay.
I'll put it that way. Yeah.
Okay. Which, I guess, in terms of the target population that you may test before.
Yeah.
Yeah.
Yeah. We go into a phase I experience first. We'd have the opportunity to go into a similar bed rest PD type design as well.
Okay.
Then we'd go right to that obesity combo study to show the additive benefit on top of an incretin drug in a broad population.
Right. Got it. In current drug, we have tirzepatide, semaglutide. Is there any preference for one versus the other?
Probably an oral.
Okay.
Because we think that's where this will shine. We haven't committed to any of that yet.
Got it.
Mechanistically, it shouldn't make much of a difference. Yeah.
Got it. Maybe on the strategic side, you had a partnership with Lilly and Novartis as well. Maybe just talk about what does that entail?
Yeah, sure. That's really because of our data sets. The way that we decide on what targets we work on at the company is we have human longitudinal data like UK Biobank, but with one key difference, it's a lot longer. We have blood samples drawn from people, the same people over 60 years of their lives, tied to long-term health outcomes like diseases, but even how long they ultimately live. We do proteomics, metabolomics on those samples. That lets us ask questions like what's different about people who evade disease until they're 90, until they're 100, and can we drug any of those pathways? That's how we got excited about NLRP3 and apelin, because we see a very nice human signal there, and that's also sort of what's driven these collaborations. Novartis, for example, it's really a data science collaboration.
They have a department of aging biology, aging-related diseases. They want to use our data to find novel targets to develop drugs against targets that no one has drugged before. We're using our human aging data, and they have, interestingly, the human response to exercise, some of the genomics and genetics of that. We're overlaying the two really to find more targets like apelin that sort of decline as you get older but are then responsive to exercise, which is still the best aging intervention. There's an upfront, there's milestones. They're supporting FTEs at the company. It's a great way to keep our early discovery side well-funded. Some of those targets will be developed by Novartis, some by BioAge, and there'll be milestones, royalties on either side. With Lilly, it's different.
We selected a couple novel targets from our platform that are really promising. They're helping us build molecules against them that we would then bring in, that we could then bring in and develop ourselves to really expand our pipeline.
Have you talked about the, I guess, in the Lilly collaboration, what therapeutic categories would that be?
Yeah, we haven't disclosed that, but the general focus is cardiometabolic.
Okay.
Yeah.
Got it. Given you have this platform in terms of your own internal pipeline, apart from apelin as well as NLRP3, anything that we should be looking for, let's say, in the next few years?
Yeah. We will only speak about things when they get really close to the clinic. But, it was our own internal efforts that led to our molecules for NLRP3 and apelin, and there are other efforts for other targets underway. We would expect those to graduate over time, too.
Okay.
Yeah.
Remind us about the IP for NLRP3, BGE-102.
Sure. Yeah. No, we have our patent granted last year. It is pretty strong, too, from a chemistry perspective. We actually discovered a novel binding site to NLRP3, so it is a pocket that only we have, and there is actually a granted claim to other things that bind in that pocket in the patent.
Okay.
Yeah.
Got it. Remind us about the cash, the runway that you have, and what trials does it cover?
Yeah. Our last guidance was about $380 million of cash at the end of the second quarter. We are really well-funded, well into 2029, with all the milestones we have discussed, an NLRP3, the DME trial, the QUELL-CV trial, as well as one or two other indications, should we choose to add them. On the APJ side, taking both the oral and the parenteral to the clinic.
Okay, got it. Maybe in the last minute or so, given the focus on IL-6 and Novo's ZEUS and the other trials, I guess, what are investors missing about the biology story right now?
Yeah, sure. I think that NLRP3, we touched on this a little bit at the beginning. There is a lot of therapeutic areas where an IL-6 or an IL-1 is approved. Even an oral agent of the same would already be an exciting value proposition. I think a lot of the education has been around cardiovascular, but now there is a lot more to learn about. For BioAge specifically, we want to do more education on the ocular indications. I think this is a more novel target there. People do not necessarily are familiar with the biology. I will point out, we did an R&D day a while ago, so we will probably bring out some of those KOLs again, because at the time, everyone was so CV-focused.
Yeah.
We think there's really a lot of opportunities for this target, and the retina is especially where we're excited about today. Yeah.
Got it. No, that's great. I know we're almost out of time, so again, thank you so much, Kristen, for joining us today. Great discussion, and looking forward to the next set of updates as well. Thank you so much.