BioAge Labs, Inc. ($BIOA)

Good afternoon, everyone. Thank you for joining us. Really pleased to have with us the BioAge Age team. We have BJ Sullivan, Chief Strategy Officer; and Dov Goldstein, CFO. To start here, the company is developing its NLRP3 inhibitor BGE-102 in cardiovascular risk and ophthalmology and also advancing a pipeline of APJ agonist. Can you walk us through the portfolio strategy where the assets stand today and the data expected over the next 12 months?

Yes. 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 BGE-102. It's a potential best-in-class NLRP3 inhibitor. So we recently released our full Phase I data, which included 2 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, you know, IL-6 in particular, that's currently in development for ASCVD. And so we have an oral modality where there's really no trade-off 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 II study that will 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, BGE-102 is our lead program. We're also developing both an oral and parenteral APJ agonist. This is the target for the [ exarkineapolin ] and that's one of the strongest signals in our platform. 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 can essentially double weight loss and fully restore body composition back to that of lean control animals when you add it to an [indiscernible]. So when thinking about the obesity market as it's evolving, the unmet needs on the oral side, probably still more the quantity of weight loss and getting that quantum on par with what we're seeing in the injectables, the injectables now we're seeing bariatric surgery like weight loss, perhaps the sort of predominant value proposition there is body composition. But we're developing both an oral in a subcutaneous agonist to complement both sort of ongoing segments of that market.

Great. And you have collaborations right now with Novartis and [indiscernible] specifically, elaborate maybe on the therapeutic focus here and how partners leverage your platform in the financial terms?

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 and health records and so we can look and actually do apply [ modernomix ] now to Bio bank samples and ask the question, 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 exercised interventional data sets that they're contributing. And so we're really looking for targets that sit at the intersection of those 2 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 in 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?

Yes. 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 convert it 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 [ aperosclerotic ] disease progression. [indiscernible] hyperglycemia is the key trigger, right? And that's been converted into sort of a cytokine cascade that drives the disease forward. But 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. Originally, the MCC950 was the original tool compound. It bound in the ATPAs pocket and groups have been creating derivatives of that, that compound novel chemotypes that target the same binding site. But what we did was we took a step back and actually did DNA-encoded library where we lock that binding site to identify novel binding side. So what we have is a -- not only totally novel chemistry, but a novel binding site that we characterized and detailed sort of structural biology of it. And as a result, we have issued IP that includes not just sort of the specific structures described that broadly speaks to the 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 MCC950 and the derivatives thereof, which are only -- the pockets 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 [indiscernible].

With regard to your Phase I data that you've shown here, you reported up to 86% reduction in CRP within 2 to 3 weeks in obese subjects with high baseline CRP, how does that compare with other inhibitors or inflammasome targeting therapies in development?

Yes. So I think we look at the sort of differentiation across 3 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 -- to the [indiscernible] in both of the cohorts that we tested in our Phase I [indiscernible] we were able to normalize CRP below the 2 mg per liter threshold in 87% to 93% of those participants. And that's really important because we learned from the CANTOS trial, which Novartis ran with our IL-1 beta antibody, showing that essentially the headline number in the MACE trial was 15%, which is a good result. But it was concentrated in the patients who achieved this 2 mg per liter threshold where they had a 25% benefit and those that didn't had essentially [indiscernible]. So we think that, that's the really meaningful outcome. And regardless of baseline in the 2 cohorts who were able to normalize them to these -- the vast majority of patients to this important [indiscernible]. So we're thrilled with the biomarker efficacy, the safety tolerability was, in our view, exceptional coming out of the Phase I trial, really no observations of any kind. And then importantly, dosing, I think, we have a clear low dose QD profile, which is not only commercially very important when you think about the ASCVD opportunity in particular, where it's dominated by orals. It's mostly PCPs prescribing. People are used to taking a [indiscernible] every day. So it's commercially very important. And then also in terms of like ultimately, strategic interest, there's a lot of value potentially in fixed-dose combinations sort of life cycle management strategies and the ability to combine NLRP3 with PCSK9, a statin and sort of, again, drive value for across the 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, can extend the Phase I data, right? So we were -- the primary outcome is CRP reductions. What we're looking to see here is a sustained decrease in CRP and other inflammatory biomarkers. We're hoping to extend the safety tolerability findings from the Phase I. And we're also adding additional assessments like MRI imaging of the liver, where [ Ventix ] previously showed, for example, benefit as a monotherapy in liver inflammation. So there will be additional assessments there. The key outcome beyond that is really dose selection. As we think about the profile coming out of Phase I, we feel like we're feeling really bullish about it. And we want to maintain an aggressive time line going forward to enable a Phase III start next year. And so part of that was expanding the Phase II POC to include exploration of multiple doses, have confidence in what we ultimately carry forward into Phase [indiscernible].

You talked about the dose the dosing work that you've done and you're looking at the 90-milligram in Phase II versus the 120-milligram in Phase I. What gives you confidence in achieving similar biomarker outcomes with the lower dose in the Phase II?

Right. So we're -- 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 in the Phase I with 120 milligrams, we saw a 98% suppression of IL-1 beta at a week. We'll achieve that level at a month in the Phase II trial, but this is really a chronic medicine. And so again, it's sort of a pharmacokinetic extrapolate. The endpoint for the study to be [indiscernible].

The key read through this year, we were just talking about this, is the Phase III 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?

Right. I mean so we're really looking for any significant MACE benefit here. I think, typically, a clinician's view 15% MACE benefit is sort of the threshold at which there's excitement. So we're looking obviously for a meaningful MACE benefit here. I would say the way we think about this is actually the biology is probably more derisked 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 had -- who achieved sort of target CRP levels at 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 locking that provides clinical benefit for patients. And so that is, of course, broadly [indiscernible]. The way we think about this program, in particular, and the value of success in ZEUS is really anticipating the launch of IL-6 in this space. I think right now, physicians only have low-dose [ colgasine ] which is approved for inflammatory cardiovascular risk, has a lot of tolerability and drug interactions that make it used in clinical practice virtually now. 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 very powerful in sort of market development or subsequent launch of an oral that can provide similar benefit in a more convenient [indiscernible].

And if the ZEUS study is unfavorable with regard to that outcome here, what is the read-through for you?

Yes. I mean, again, I think we map the biology more closely to CANTOS trial, but we won't swim upstream if it's sort of catastrophic negative result, but we're cautiously [indiscernible].

The primary focus of the CV risk market has been LDL lowering with PCSK9 in statins with increasing focus on LPA as a target coming up. Where do you therapies targeting residual inflammation fit? And what is the market opportunity in that context?

Yes. So this is -- there was actually a really compelling paper in the New England Journal of Medicine, I believe, last year by [ Paul Ridker ] is 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 that target CRP level of 2 mg per liter. So we think that this is -- we're hoping that this will become a routine part of care where those patients who do have elevated CRP despite whatever background therapy they are on will be initiated on a drug that can address that risk because, again, it's highly predictive and it is independent on these other sort of lipid biomarkers.

And you plan to start a Phase III by year-end '27. Do you plan to advance independently or seek a partner here?

Yes. So I mean, I think right now, our focus is on enablement, I would say, all of the long lead time activities that we need to feel confident with this aggressive timing. So that includes doing dose ranging. It includes initiating a [ CNC ] campaign to support the initiation of a trial of that size. And of course, aligning on the design and all of the preparation for an end of Phase II meeting. But Dov, do you want to speak to the partnership aspect?

Yes, 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 ourselves. And that means, as PJ 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 ASCVD.

Perfect. Let's switch over to ophthalmology here with 102. With regard to diabetic macular edema and geographic atrophy, maybe 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 I data, we show that we get excellent CSF penetration. We've shown in a range of preclinical species that we get therapeutic exposure in the retina. And so we're leaning into the of the molecule to sort of expand the scope of 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 to cellular [indiscernible] like drusen, which has these amyloid components. And so you get deposition of all of the cellular [indiscernible] and it's sort of a canonical pro-inflammatory trigger. So NLRP3 actually sits at the core of both of those diseases, but with different upstream drivers.

And any read-through from [ Roche's ] data for their IL-6?

Yes. So the [indiscernible] 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 in an intravitreal injection, right, and they've shown efficacy now as a monotherapy with over a line. 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 benefit in this patient population. It also showed that essentially the maximum benefit was achieved by 2 months of treatment. And so for us, thinking about attractable POC indication where we're trying to, first and foremost, demonstrate target engagement in the eye, 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, it's one of the -- it's one aspect of NLRP3. It's not the totality of the picture. I think NLRP3 does induce IL-6. It also VEGF is induced by IL-1 beta. You've got this sort of [indiscernible] cell death when NLRP3 is activated and the retinal [indiscernible]. And so there is potential to have efficacy beyond what we've demonstrated with these IL-6 modalities. And of course, without the sort of the complications that come with that [indiscernible].

For the DME study, we were 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 in the incremental BCVA in each of those cases?

So our POC study, it's going to have 3 arms. We're looking at BGE-102 as a monotherapy. We're also looking at VEGF as a monotherapy in VEGF combined with BGE-102. So there are 3 arms we're going to treat for 2 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 [indiscernible]. 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 a biomarker primary, but 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 change, right, thinking about that pharmacodynamic of that.

And where would this drug be positioned within 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 patient. So they're 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 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 the sort of -- you sort of got early patients and then I think also late patients where you've got -- they've been on VEGF, they're refractory in terms of the [indiscernible] 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, the convenience of a secondary [indiscernible].

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 doing that?

Yes. I mean that's, of course, the treatment [indiscernible]. I mean -- but the -- but yes, so geographic atrophy is -- is this essentially the terminal stage of dry AMD. It causes central blindness in the vast majority of patients. And there are approved complement inhibitors, so [indiscernible]. They -- 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, and oral less convenient, especially with the 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 [indiscernible].

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.

Yes. So as we demonstrated in the Phase I, we do get really, really nice CNS exposure with the drug. Right now, we're very focused on ophthalmology as our way to lean into the sort of differentiated distribution of the drug. But thinking long term and the applicability of this mechanism, really, the range of neurodegenerative conditions, in particular, are exciting because those are ones where you get accumulation of debris like [ alpha-synuclein or amyloids ] and then those are nonoculagain, pro-inflammatory trigger. So it's a lot for a small biotech to block and tackle, but there's a lot of promise in this mechanism for this sort of broader range of [indiscernible].

And then finally, [indiscernible] where it all started, but you do have an agonist here under development, one in collaboration with [indiscernible]. In terms of therapeutic areas and focus, speak to expected profile and key near-term milestones.

Yes. So we are developing 2 APJ agonists, one for an oral small molecule and then a subcutaneous agonist as well as you mentioned, we have a collaboration with GKN Therapeutics, developing agonist nanobody. And the profile here, again, is we're looking to increase both the quantity and quality of weight loss. And so we think that even as the obesity market evolves, I think a lot of key unmet needs remain. And so thinking about the oral space were incremental efficacy to really make it a competitive alternative to an injectable, it would be commercially valuable with body composition is sort of a nice upside. I would say, too, with limited increase in GI tolerability, I think our experience with this target is that it shouldn't lead to any sort of on tolerability issues that would make combinations with [indiscernible] challenging. And I think that that's in contrast to other sort of mechanisms focused on certainly [indiscernible]. So on the parenteral side, injectables have achieved remarkable amounts of weight loss, but I think body composition, especially addressing that in a well-tolerated remains a major unmet need. And so this is, again, where we're -- the optimal profile for a subcu would be to complement the injectable increase. I mean you could even think about [indiscernible] to sort of take advantage of some of the synergistic weight loss, but either of those, I think, would be highly valuable.

Great. 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?

Yes. My pleasure. So at the end of the first quarter, we had $385 million of cash. All the 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 1 of these 2 indications will be another molecule to split the commercial opportunity. But with all the programs we've talked about, we have cash runway into 2026.

And why would you -- just maybe the rationale for the second follow-on in NLRP3 and the need to split the commercial?

Yes, I'm just thinking about if we partner ASCVD asset with someone and want to price it at a certain level and want to keep ophthalmology for ourselves and prices are different gives us that flex [indiscernible].

Perfect. Well, with that, thank you so much.

Thank you very much, Salveen.

Thank you so much.