Good afternoon, everyone. Thank you for joining us. Really pleased to have with us the BioAge team. We have B.J. Sullivan, Chief Strategy Officer, and Dov Goldstein, CFO. To start here, the company's developing its NLRP3 inhibitor, BGE-102, and cardiovascular risk and ophthalmology, and also advancing a pipeline of APJ agonists. Can you walk us through the portfolio strategy, where the assets stand today and the data expected over the next 12 months.
Yeah, one, thank you for having us. Great to be here. So we are a clinical stage biotech company, and we are applying human aging biology as a lens for target discovery and development of therapies for cardiometabolic disease. As you mentioned, our lead program is BG102. It's, you know, a potential best-in-class NLRP3 inhibitor. So we recently released our full Phase I data, which included two cohorts of obese subjects with elevated inflammation at baseline, and there we showed CRP reductions of 86% in both cohorts, which was really exciting for us because that essentially is on par with the CRP reductions that have been shown with the injectable modalities, IL-6 in particular that's currently in development for ASCVD. And so we have an oral modality where there's really, you know, no tradeoff now in anti-inflammatory sort of horsepower. So I'm sure we can go into those results in more detail, but we're developing this. Our anchor therapeutic area is cardiovascular disease. We're doing a cardiovascular risk proof of concept dose ranging phase two study that I'll read out by the end of this year. And our second therapeutic area, which we introduced earlier this year, is ophthalmology. and we're doing a DME proof of concept study to really demonstrate target engagement in the eye and we're going to initiate that study in the middle of this year and have results in the middle of next year. So again, BG-102 is our lead program. We're also developing both an oral and a parenteral APJ agonist. This is the target for the exerkin apolin and that's one of the strongest signals in our platform. You know, it's associated not only with longevity, but also preservation of physical function. This is an extra kind that is secreted by muscles during exercise. And what we've shown preclinically is that, you know, you can essentially double weight loss and fully restore body composition back to that of lean control animals when you add it to an incretin. So when thinking about, you know, the obesity market as it's evolving, you know, the unmet needs on the oral side, you know, probably still more the quantity of weight loss and getting that quantum on par with what we're seeing in the injectables, you know, the injectables now we're seeing bariatric surgery like weight loss, perhaps the sort of predominant value proposition there is body composition, you know, but we're developing both an oral, you know, and a subcutaneous agonist to complement both sort of ongoing segments of that market.
Great. And you have collaborations right now with Novartis and Eli Lalit specifically. Elaborate maybe on the therapeutic focus here and how partners leverage your platform in the financial term.
Right. So we had a target discovery partnership with Novartis. And so this is looking for targets that sit at the intersection of healthy aging and exercise. And so what we built at the company is one of the world's largest collections of human aging data, which really look at healthy middle-aged people and then track them essentially to death with very detailed phenotyping, you know, and health records. And so we can look and actually do apply modernomics now to biobank samples and ask the question, you know, what is the biology that predicts not only longevity, but sort of very granular health outcomes and phenotypes. And so that's the data set that we contribute to the collaboration, and Novartis has exercise interventional data sets that they're contributing. And so we're really looking for, you know, targets that sit at the intersection of those two things. We also have a collaboration with Lilly, and that's really focused on molecule discovery. And so we're building drugs against targets that we've identified in our platform.
So starting with 102 here, can you explain the role of NLRP3, the inflammasome pathway, in your inflammation and cardiovascular disease? And you've talked about a novel binding site versus other drugs in this class. So how does this translate to differences in efficacy and safety?
So NLRP3 is one of the inflammasomes in the body. And essentially, it is a sensor and a transducer of signals that contribute to sterile inflammation. So if you think about in the ASCVD context, this is cholesterol crystals, oxidized LDL, metabolic stress, hyperglycemia. All of those are essentially sensed by NLRP3 and then converted into sort of a cytokine cascade, right? So NLRP3 regulates the production of IL-1 beta, of IL-18. It also controls pyroptotic cell death and atherosclerotic disease progression. You know, in the eyes, hyperglycemia is the key trigger, right? And that's then converted into sort of a cytokine cascade that drives the disease forward. But, you know, yes, so again, this is one of several inflammasomes in the body, but it is the primary contributor to sterile inflammation. People have been trying to drug this for 20 years now. You know, originally, MCC-950 was the original tool compound. It found in the ATPase pocket, and groups have been creating derivatives of that, that compound, novel chemotypes that target the same binding site. You know, but what we did was we took a step back and actually did, you know, a DNA-encoded library where we blocked that binding site to identify novel binding sites. So what we have is a not only totally novel chemistry, but a novel binding site that we characterized in detail, the sort of structural biology of it. And as a result, we have issued IP that includes not just sort of the specific structures described, but broadly speaks to ligands that interact with that binding site. And what's interesting about it is that it can bind NLRP3 in any confirmation. So whether it's active or inactive, our pocket is accessible, which is unlike MCC-950 and the derivatives thereof, which are only, the pocket's only available when it's in the inactive form. And that may contribute to either onset of action as well as sort of the magnitude of the anti-inflammatory effect that we're observing. Essentially, all of the NLRP3 in the body is open to our foreign hip.
With regard to your phase one data that you've shown here, you reported up to an 86% reduction in CRP within two to three weeks in obese subjects with high baseline CRP. How does that compare with other inhibitors or inflammasome targeting therapies in development?
So I think we look at the sort of differentiation across three key dimensions. So one is efficacy in terms of biomarker reductions, safety and tolerability, as well as dosing. And so to speak first to the bio, in both of the cohorts that we tested in our phase one, we were able to normalize CRP, you know, below the two migs per liter threshold in 87 to 93 percent of those participants. And that's really important because we learned from the Cantos trial, which Novartis ran with our IL-1 beta, you know, antibody showing that, you know, essentially the headline number in the MACE trial was 15%, which is a good result, you know, but it was concentrated in the patient to achieve this 2 mg per liter threshold where they had a 25% benefit, you know, and those that didn't had essentially none. So we think that that's the really meaningful outcome. And, you know, regardless of baseline, you know, in the two cohorts who were able to normalize them to these, you know, the vast majority of patients to this important role. So we're, you know, thrilled with the biomarker efficacy. You know, the safety tolerability was, you know, in our view, exceptional coming out of the phase one trial, really no observations of any kind. And then importantly, you know, dosing, I think. You know, we have a clear low-dose QD profile, which is not only commercially very important And when you think about, you know, the ASCVD opportunity in particular, where it's dominated by orals, it's mostly PCPs prescribing, people are used to taking a statin every day.
So it's commercially very important.
And then also, you know, in terms of, like, you know, ultimately strategic interest, there's a lot of value, potentially, in fixed-dose combinations, and the sort of life cycle management strategies and the ability to combine NLRP3 with an oral PCSK9, a statin, and sort of, you know, again, drive value for across a franchise, but also maximize sort of patient acceptance and convenience.
So given these Phase I data, what are expectations for Phase II proof-of-concept data that's coming by year end?
So the proof-of-concept is really first and foremost going to extend the phase one data, right, so we were, the primary outcome is CRP reductions. What we're looking to see here is we sustained decrease in CRP and other inflammatory biomarkers. We're hoping to extend the safety tolerability findings from the phase one, and we're also adding additional assessments like MRI imaging of the liver, where Ventix previously showed, for example, you know, benefit as a monotherapy in liver inflammation. There will be additional assessments there. The key outcome beyond that is really dose selection. You know, as we think about the profile coming out of phase one, we feel like it, you know, we're feeling really bullish about it. And we want to, you know, maintain an aggressive timeline going forward to enable a phase three start next year. And so part of that was expanding the phase two POC to include exploration of multiple doses, have confidence in what we ultimately carry forward into phase one.
You talked about the dose, the dosing work that you've done, and you're looking at the 90 milligram in phase two versus the 120 milligram in phase one. What gives you confidence in achieving similar biomarker outcomes with the lower dose in the phase two?
Right. So the top dose in the dose-ranging study is 90 milligrams QD, and we are expecting on an exposure basis that that's really going to give us 98% target suppression. So the drug does have a relatively long half-life and reaches steady state at about a month. And so the difference between the 120 milligram and 90 milligram dose is really an adjustment for that PK profile, right? So, you know, in the phase one with 120 milligrams, we saw 98% suppression of IL-1 beta at a We'll achieve that level at a month in the phase two trial, but this is really a chronic medicine. And so, again, it's sort of a pharmacokinetic extrapolation.
The end point for the study is to be done.
The key read-through this year, we were just talking about this, but it's the phase 3-CV outcomes data for Novo's IL-6 inhibitor in the Zeus trial. What level of MACE reduction would bode well for your drug and for the class overall?
I mean, so we're really looking for any significant MACE benefit here. I think typically clinicians view 15% MACE benefit as sort of the threshold at which there's excitement. So we're looking, obviously, for a meaningful MACE benefit here. I would say that the way we think about this is actually the biology is probably more de-risked by the Cantos trial that we were talking about earlier, which is targeting IL-1 beta, which is directly downstream of NLRP3 and where patients who achieved sort of target CRP levels had a 25% mace benefit, but of course, if IL-6 shows a significant benefit here, you're saying that no matter where you are in this inflammatory cascade, that blocking that provides clinical benefit for patients, and so that is, of course, broadly significant. You know, the way we think about this program in particular, and the value of success in Zeus is really anticipating a launch of an IL-6 drug in this space. I think right now, physicians only have low-dose colchicine, which is approved for inflammatory cardiovascular risk, has a lot of tolerability and drug interactions that make its use in clinical practice virtually enough. And so the prospect of having a selective anti-inflammatory launch in the space, have growing physician awareness of inflammation as a treatable risk factor, and have CRP routinely tested as part of your sort of annual workup. We think all of those would be, you know, very powerful in sort of market development for subsequent launch of an oral that can provide similar benefits in a more convenient sort of form.
And if the Zeus study is unfavorable with regard to that outcome here, what is the read-through for you?
Yeah, I mean, again, I think we map the biology more closely to the Cantos trial, but we won't swim upstream if it's a sort of catastrophic, you know, negative result, but, you know, we're cautiously up.
The primary focus of the CV risk market has been LDL lowering with PCSK9s and statins with increasing focus on LPLA as a target coming up. Where do therapies targeting residual inflammation fit, and what is the market opportunity in that context?
So this is, there was actually a really compelling paper in the New England Journal of Medicine, and I believe last year by Paul Ritger showing that HSCRP was actually the most predictive risk factor for MACE in the 30-year longitudinal women's health study. And so it's a strong risk factor. It's an independent risk factor. And it's one where there's actually about 60% of ASCVD patients today have residual inflammatory risk, which is to say they have not achieved, you know, that target CRP level of 2 mg per liter. You know, so we think that this is, you know, we're hoping that this will become a routine part of care where, you know, those patients who do have elevated therapy, despite, you know, whatever background therapies they're on, you know, will be initiated on a drug that can address that risk. Because, again, it's highly predictive and it is independent, you know, these other sort of lipid biomarkers.
And you plan to start a phase three by year end. 27, do you plan to advance independently or seek a partner here?
Yeah, so I mean, I think right now our focus is on enablement, I would say. You know, all of the long lead time activities, you know, that we need to feel confident, you know, with this aggressive timing. So that includes doing dose ranging. It includes initiating a CMC campaign to support the initiation of a trial of that size. And, of course, aligning on a design and all of the preparation for an NFA's two meeting. But, Doug, do you want to speak to the partnership aspect?
Yeah, sure. My pleasure. So as far as partnership, we strongly believe the best way to form a partnership potentially is for the company to be in a strong position to go at ourselves. And that means, as BJ mentioned, preparedness, but also financial preparedness. This is an asset that makes sense already in the late-stage clinical setting to be done by a larger group, but we are prepared as a company.
Anything else we need to touch on with regard to this program?
I think we've covered the bases in ASCBD.
Let's switch over to ophthalmology here with 102. With regard to diabetic macular edema and geographic atrophy, may we speak to the mechanistic rationale behind moving into these disease areas? Right, right.
So I think that there's one sort of driver of sort of our therapeutic area strategy here is just the differentiation of the molecule and the ability to access these privileged compartments and the distribution profile of the molecule. So in our phase one data, we show that we get excellent CSF penetration. You know, we've shown in a range of preclinical species that we get therapeutic exposure in the retina. And so we're leaning into the property of the molecule to sort of expand the scope of, you know, indications that we can address. and ophthalmology is sort of our second anchor therapeutic area. So to speak to the biology of it, the NLRP3, again, is a sensor of sterile inflammatory triggers. In DME, it's really responding to hyperglycemia, and that's what activates NLRP3. Geographic atrophy is a little bit different. It's almost like a neurodegenerative condition of the retina where you get accumulation of the cellular debris, like gerucin, which has these amyloid components. And so you get deposition of all of the cellular debris, and it's sort of a canonical pro-inflammatory trigger. So NLRP3 actually sits at the core of both of those diseases, but, you know, with different upstream drivers.
And any read-through from Roche's data for their IL-6?
Yeah. So the VamiQBAR program has been sort of informative for us in thinking about our next steps here. I think, first and foremost, this is an IL-6 intravitreal injection. And they've shown efficacy now as a monotherapy with Overalign. They released that data at Arvo a few weeks ago. They had shown incremental efficacy on top of VEGF. So I think on a very fundamental level, it tells us that selective anti-inflammatory strategies can provide incremental benefits in this patient population. It also showed that essentially the maximum benefit was achieved by two months of treatment. And so for us thinking about, you know, attractable POC indication where we're trying to, you know, first and foremost demonstrate target engagement in the eye, you know, that this is a tractable indication for us versus geographic atrophy, which is an area of enormous unmet need, but it does progress more slowly. I think in thinking about IL-6, though, you know, it's one of the, it's one aspect of NLRP3. It's not the totality of the picture. I think, you know, NLRP3 does induce IL-6. It also, you know, VEGF is induced by IL-1 beta. You've got this sort of pyreptotic cell death when NLRP3 is activated and, you know, the retinal microvasculature. And so there is potential to have, you know, efficacy beyond what was demonstrated with these IL-6 modalities. And, of course, without the sort of the complications that come with that root of administration.
For the DME study, we're looking forward to results in mid-2027 here. What percentage change in intraocular IL-6 will be clinically meaningful? And maybe talk about both the monotherapy in combination with anti-VEGF therapy and the incremental BCVA in each of those cases.
So our POC study, it's going to have three arms. We're looking at BG-102 as a monotherapy. We're also looking at VEGF as a monotherapy in VEGF combined with BG-102. So there are three arms we're going to treat for two months. And the primary endpoint is the percent change in IL-6, intraocular IL-6. So we're going to be doing aqueous taps on these patients so we can measure biomarkers in the aqueous fluid. You know, we're powering the study for about a 40% change in IL-6, but I think it's going to be important for us to look at the totality of the data. So it will be, you know, a biomarker primary, but, you know, we're going to be doing functional assessments like BCVA. We'll be making anatomical OCT measurements like CST, and so we're going to be looking to see that the totality of the data sort of tracks that biomarker chain, right, thinking about,
you know, that pharmacodynamics. And where would this drug be positioned within the market? So I think that there are multiple compelling segments here.
So if you think about DME, I think the obvious segment is the watch and wait patients. So there are about 40% of DME patients who have edema, but they don't have sufficiently compromised vision that ophthalmologists have initiated intravitreal therapy. And so if you can treat these patients with an oral and delay the onset of initiation of that therapy, that could be incredibly meaningful. I mean, I think, you know, for context, VEGF does work well in a lot of patients, especially in trials. I think in the real world, that picture becomes more complicated because you're talking about monthly or quarterly dosing that's challenging for sort of working average people follow. So that's sort of one highly addressable segment. On the other side of this, sort of, you sort of got early patients and then I think also late patients where you've got, they've been on a VEGF, they're refractory in terms of the amount of disease control, even when they're compliant. So adding on this mechanism to regain disease control would be very meaningful, and I think there it's really just the clinical benefit, first and foremost, and the convenience of
For geographic atrophy, I mean, this has been a much harder indication historically than DME, particularly with regard to BCVA. What is the expected profile for your drug in geographic atrophy, and can the drug deliver functional improvement, noting the absence of approved assets, as we just mentioned, showing that.
I mean, that's, of course, the treatment call. I mean, but yeah, so geographic atrophy, this is essentially the terminal stage of dry AMD. It causes central blindness in the vast majority of patients, and, you know, there are approved complement inhibitors, so Sifovir and Iservae. They, you know, these are blockbuster products, but they, right now they slow lesion size by about 15%, right? And they require monthly injections. They haven't shown visual acuity benefits yet.
So there's a ton of unmet need here.
I mean, the clinical need is really enormous. And so in thinking about the positioning of this molecule, yes, an oral is convenient, especially with this sort of majority elderly population. But just getting disease control of any kind, however you measure it, I think is a major step forward for these gins.
You've also talked about going into CNS-related chronic inflammatory conditions. Speak to the rationale there and the indications that may be of most interest.
Yeah, so as we demonstrated in the phase one, we do get really, really nice CNS exposure with the drug. You know, right now we're very focused on ophthalmology as our way to lean into the sort of differentiated distribution of the drug. But, you know, thinking long-term and the applicability of this mechanism, you know, really the range of neurodegenerative conditions in particular are exciting because those are ones where you get accumulation of debris like, you know, alpha-synuclein or, you know, amyloids, and those are canonical, again, pro-inflammatory triggers. So, you know, it's a lot for a small biotech to block and tackle, but there's a lot of, you know, promise in this mechanism for this sort of broader range of CNSs.
And then finally, APLIN, where it all started. But you do have an agonist here under development, one in collaboration with GKANG. In terms of therapeutic areas in focus, speak to expected profile and key nurture milestones.
Yeah, so we are developing two APJ agonists, one for an oral small molecule, and then a subcutaneous agonist as well, as you mentioned. We have a collaboration with GK Therapeutics developing the agonist nanobody. And, you know, the profile here, again, is, you know, we're looking to increase both the quantity and quality of weight loss. And so, you know, we think that even as the obesity market evolves, you know, I think a lot of key unmet needs remain. And so thinking about, you know, the oral space for incremental efficacy to really make it a competitive alternative to an injectable, it would be, you know, commercially, you know, valuable, you know, with body composition, you know, as sort of a nice upside. You know, I would say, too, with limited increase in GI tolerability, I think, you know, our experience with this target is that it shouldn't lead to any sort of intolerability issues that would make combinations with Inquitans challenging, and I think that that's in contrast to other sort of mechanisms focused on certainly anabolism. So, you know, and on the parenteral side, you know, injectables have achieved remarkable amounts of weight loss, but I think body composition, you know, and especially addressing that in a well-tolerated way remains a major unmet need. And so this is, again, you know, where the optimal profile for a sub-Q would be, you know, to complement the injectable increase. I mean, you could even think about dose-bearing, too, to sort of take advantage of some of the synergistic weight loss, but, you know, either of those, I think, would be highly valuable, right?
And maybe just here as a final question, walk us through your cash position and cash runway and maybe just in the context of all these programs that you're advancing.
Yeah, my pleasure. So at the end of the first quarter, we had $385 million in cash. All the programs we've outlined are included in the guidance I'm just about to give you. The only thing we haven't talked about is we're actively working on a backup compound for NLRP3 to potentially one of these two indications will be another molecule to split the commercial opportunity. But with all the programs we've talked about, we have cash run away into 2020.
Why would you just maybe the rationale for the second follow-on NLRP3 and the need to
Yeah. Just thinking about if we partner the ASCV asset with someone and want to price it at a certain level and want to keep ophthalmology for ourselves and price it at different, it gives us that flexibility.
Perfect. Well, with that, thank you so much.
Thank you very much. Thank you so much.